Amino-5-[4-(difluoromethoxy)phenyl]-5-phenylimidazolone compounds for the inhibition of β-secretase

ABSTRACT

The present invention provides a 2-amino-5-[4-(difluoromethoxy)phenyl]-5-phenylimidazolone compound of formula I 
     
       
         
         
             
             
         
       
     
     The present invention also provides methods for the use thereof to inhibit β-secretase (BACE) and treat β-amyloid deposits and neurofibrillary tangles.

This application claims the benefit under 35 U.S.C. § 119(e) to U.S.provisional application No. 60/720,589, filed Sep. 26, 2005, which ishereby incorporated by reference in its entirety.

BACKGROUND

β-Amyloid deposits and neurofibrillary tangles are two major pathologiccharacterizations associated with Alzheimer's disease (AD). Clinically,AD is characterized by the of loss of memory, cognition, reasoning,judgment, and orientation. Also affected, as the disease progresses, aremotor, sensory, and linguistic abilities until global impairment ofmultiple cognitive functions occurs. These cognitive losses take placegradually, but typically lead to severe impairment and eventual death in4-12 years.

Amyloidogenic plaques and vascular amyloid angiopathy also characterizethe brains of patients with Trisomy 21 (Down's Syndrome), HereditaryCerebral Hemorrhage with Amyloidosis of the Dutch-type (HCHWA-D), andother neurodegenerative disorders. Neurofibrillary tangles also occur inother neurodegenerative disorders including dementia-inducing disorders(Varghese, J., et al, Journal of Medicinal Chemistry, 2003, 46,4625-4630).

β-amyloid deposits are predominately an aggregate of Aβ peptide, whichin turn is a product of the proteolysis of amyloid precursor protein(APP). More specifically, Aβ peptide results from the cleavage of APP atthe C-terminus by one or more γ-secretases, and at the N-terminus byβ-secretase enzyme (BACE), also known as aspartyl protease, as part ofthe β-amyloidogenic pathway.

BACE activity is correlated directly to the generation of Aβ peptidefrom APP (Sinha, et al, Nature, 1999, 402, 537-540), and studiesincreasingly indicate that the inhibition of BACE inhibits theproduction of Aβ peptide (Roberds, S. L., et al, Human MolecularGenetics, 2001, 10, 1317-1324).

Therefore, it is an object of this invention to provide compounds whichare inhibitors of β-secretase and are useful as therapeutic agents inthe treatment, prevention or amelioration of a disease or disordercharacterized by elevated β-amyloid deposits or β-amyloid levels in apatient.

It is another object of this invention to provide therapeutic methodsand pharmaceutical compositions useful for the treatment, prevention oramelioration of a disease or disorder characterized by elevatedβ-amyloid deposits or β-amyloid levels in a patient.

It is a feature of this invention that the compounds provided may alsobe useful to further study and elucidate the β-secretase enzyme.

These and other objects and features of the invention will become moreapparent by the detailed description set forth hereinbelow.

SUMMARY OF THE INVENTION

The present invention provides a compound of formula I

wherein

-   R₁ and R₂ are each independently H or an alkyl, cycloalkyl,    cycloheteroalkyl, aryl or heteroaryl group each optionally    substituted or R₁ and R₂ may be taken together with the atom to    which they are attached form an optionally substituted 5- to    7-membered ring optionally interrupted by an additional heteroatom    selected from O, N or S;-   R₃ is H or an alkyl, cycloalkyl, cycloheteroalkyl, aryl or    heteroaryl group each optionally substituted;-   R₄, R₅ and R₆ are each independently H, halogen, NO₂, CN, COR₇,    NR₁₀CO₂R₁₁, NR₁₅COR₁₆, OR₁₄, NR₁₂R₁₃, SO_(n)R₁₇ or an alkyl,    haloalkyl, alkenyl, haloalkenyl, alkynyl, cycloalkyl or    cycloheteroalkyl group each optionally substituted or when attached    to adjacent carbon atoms R₄ and R₅ may be taken together with the    atoms to which they are attached to form an optionally substituted    5- to 7-membered ring optionally containing one or two heteroatoms    selected from O, N or S;-   n is 0, 1 or 2;-   R₇ and R₁₇ are each independently H, NR₈R₉ or an alkyl, haloalkyl,    alkoxyalkyl, alkenyl, alkynyl, cycloalkyl or aryl group each    optionally substituted;-   R₈ and R₉ are each independently H or an alkyl, alkenyl, alkynyl or    cycloalkyl group each optionally substituted or R₈ and R₉ may be    taken together with the atom to which they are attached to form an    optionally substituted 5- to 7-membered ring optionally containing    an additional heteroatom selected from O, N or S;-   R₁₁, R₁₄ and R₁₆ are each independently H or an alkyl, haloalkyl,    alkoxyalkyl, alkenyl, alkynyl, cycloalkyl or aryl group each    optionally substituted;-   R₁₀ and R₁₅ are each independently H or an optionally substituted    alkyl group; and-   R₁₂ and R₁₃ are each independently H or an alkyl or cycloalkyl group    each optionally substituted or R₁₂ and R₁₃ may be taken together    with the atom to which they are attached to form an optionally    substituted 5- to 7-membered ring optionally containing an    additional heteroatom selected from O, N or S; or    a tautomer thereof, a stereoisomer thereof or a pharmaceutically    acceptable salt thereof.

The present invention also relates to the use of such compounds for thetreatment of β-amyloid deposits and neurofibrillary tangles. The formulaI compounds are particularly useful in treating Alzheimer's disease,cognitive impairment, Down's Syndrome, HCHWA-D, cognitive decline,senile dementia, cerebral amyloid angiopathy, degenerative dementia, orother neurodegenerative disorders.

DETAILED DESCRIPTION OF THE INVENTION

Alzheimer's disease (AD) is a major degenerative disease of the brainwhich presents clinically by progressive loss of memory, cognition,reasoning, judgement and emotional stability and gradually leads toprofound mental deterioration and death. The exact cause of AD isunknown, but increasing evidence indicates that amyloid beta peptide(A-beta) plays a central role in the pathogenesis of the disease. (D. B.Schenk; R. E. Rydel et al, Journal of Medicinal Chemistry, 1995, 21,4141 and D. J. Selkoe, Physiology Review, 2001, 81, 741). Patients withAD exhibit characteristic neuropathological markers such as neuriticplaques (and in β-amyloid angiopathy, deposits in cerebral bloodvessels) as well as neurofibrillary tangles detected in the brain atautopsy. A-beta is a major component of neuritic plaques in AD brains.In addition, β-amyloid deposits and vascular β-amyloid angiopathy alsocharacterize individuals with Downs Syndrome, Hereditary CerebralHemmorhage with Amyloidosis of the Dutch type and otherneurodegenerative and dementia-inducing disorders. Overexpression of theamyloid precursor protein (APP), altered cleavage of APP to A-beta or adecrease in the clearance of A-beta from a patient's brain may increasethe levels of soluble or fibrullar forms of A-beta in the brain. Theβ-site APP cleaving enzyme, BACE1, also called memapsin-2 or Asp-2, wasidentified in 1999 (R. Vassar, B. D. Bennett, et al, Nature, 1999, 402,537). BACE1 is a membrane-bound aspartic protease with all the knownfunctional properties and characteristics of β-secretase. Low molecularweight, non-peptide, non-substrate-related inhibitors of BACE1 orβ-secretase are earnestly sought both as an aid in the study of theβ-secretase enzyme and as potential therapeutic agents.

Surprisingly, it has now been found thatamino-5-[4-(difluoromethoxy)phenyl]-5-phenylimidazolone compounds offormula I demonstrate inhibition of β-secretase and the selectiveinhibition of BACE1. Advantageously, said phenylimidazolone compoundsmay be used as effective therapeutic agents for the treatment,prevention or amelioration of a disease or disorder characterized byelevated β-amyloid deposits or β-amyloid levels in a patient.Accordingly, the present invention provides anamino-5-[4-(difluoromethoxy)phenyl]-5-phenylimidazolone compound offormula I

wherein

-   R₁ and R₂ are each independently H or an alkyl, cycloalkyl,    cycloheteroalkyl, aryl or heteroaryl group each optionally    substituted or R₁ and R₂ may be taken together with the atom to    which they are attached form an optionally substituted 5- to    7-membered ring optionally interrupted by an additional heteroatom    selected from O, N or S;-   R₃ is H or an alkyl, cycloalkyl, cycloheteroalkyl, aryl or    heteroaryl group each optionally substituted;-   R₄, R₅ and R₆ are each independently H, halogen, NO₂, CN, COR₇,    NR₁₀CO₂R₁₁, NR₁₅COR₁₆, OR₁₄, NR₁₂R₁₃, SO_(n)R₁₇ or an alkyl,    haloalkyl, alkenyl, haloalkenyl, alkynyl, cycloalkyl or    cycloheteroalkyl group each optionally substituted or when attached    to adjacent carbon atoms R₄ and R₅ may be taken together with the    atoms to which they are attached to form an optionally substituted    5- to 7-membered ring optionally containing one or two heteroatoms    selected from O, N or S;-   n is 0, 1 or 2;-   R₇ and R₁₇ are each independently H, NR₈R₉ or an alkyl, haloalkyl,    alkoxyalkyl, alkenyl, alkynyl, cycloalkyl or aryl group each    optionally substituted;-   R₈ and R₉ are each independently H or an alkyl, alkenyl, alkynyl or    cycloalkyl group each optionally substituted or R₈ and R₉ may be    taken together with the atom to which they are attached to form an    optionally substituted 5- to 7-membered ring optionally containing    an additional heteroatom selected from O, N or S;-   R₁₁, R₁₄ and R₁₆ are each independently H or an alkyl, haloalkyl,    alkoxyalkyl, alkenyl, alkynyl, cycloalkyl or aryl group each    optionally substituted;-   R₁₀ and R₁₅ are each independently H or an optionally substituted    alkyl group; and-   R₁₂ and R₁₃ are each independently H or an alkyl or cycloalkyl group    each optionally substituted or R₁₂ and R₁₃ may be taken together    with the atom to which they are attached to form an optionally    substituted 5- to 7-membered ring optionally containing an    additional heteroatom selected from O, N or S; or    a tautomer thereof, a stereoisomer thereof or a pharmaceutically    acceptable salt thereof.

It is understood that the claims encompass all possible stereoisomersand prodrugs. Moreover, unless stated otherwise, each alkyl, alkoxy,alkenyl, alkynyl, cycloalkyl, cycloheteroalkyl, aryl or heteroaryl groupis contemplated as being optionally substituted.

An optionally substituted moiety may be substituted with one or moresubstituents. The substituent groups which are optionally present may beone or more of those customarily employed in the development ofpharmaceutical compounds or the modification of such compounds toinfluence their structure/activity, persistence, absorption, stabilityor other beneficial property. Specific examples of such substituentsinclude halogen atoms, nitro, cyano, thiocyanato, cyanato, hydroxyl,alkyl, haloalkyl, alkoxy, haloalkoxy, aryloxy, amino, alkylamino,dialkylamino, formyl, carbonyl, alkoxycarbonyl, carboxyl, alkanoyl,alkylthio, alkylsulfinyl, alkylsulfonyl, carbamoyl, alkylamido, phenyl,phenoxy, benzyl, benzyloxy, cycloalkyl or cycloheteroalkyl groups,preferably halogen atoms, lower alkyl or lower alkoxy groups, wherein‘lower’ is from 1 to 4 carbon atoms. In one embodiment the substituentgroups may be selected from halo, cyano, hydroxy, alkyl, alkenyl,alkynyl, alkoxy or cycloalkyl. Unless otherwise specified, typically,0-4 substituents may be present. When any of the foregoing substituentsrepresents or contains an alkyl substituent group, this may be linear orbranched and may contain up to 12 carbon atoms, preferably up to 6carbon atoms, more preferably up to 4 carbon atoms.

As used herein, the term “alkyl” includes both straight chain andbranched-chain (unless defined otherwise) monovalent saturatedhydrocarbon moieties of 1-12 carbon atoms, preferably 1-6 carbon atoms,more preferably ‘lower’ alkyl of 1-4 carbon atoms. Examples of saturatedhydrocarbon alkyl moieties include, but are not limited to, chemicalgroups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl,isobutyl, sec-butyl; higher homologs such as n-pentyl, n-hexyl, and thelike. Alkyl groups can be optionally substituted. Suitable alkylsubstitutions include, but are not limited to, CN, OH, halogen, alkenyl,alkynyl, cycloalkyl, phenyl, carbamoyl, carbonyl, alkoxy or aryloxy.

As used herein the term “haloalkyl” designates a C_(n)H_(2n+1) grouphaving from one to 2n+1 halogen atoms which may be the same ordifferent. Examples of haloalkyl groups include CF₃, CH₂Cl, C₂H₃BrCl,C₃H₅F₂, or the like. Similarly, the term haloalkoxy designates anOC_(n)H_(2n+1) group having from one to 2n+1 halogen atoms which may bethe same or different.

The term “alkoxyalkyl” as used herein, refers to an alkyl group ashereinbefore defined substituted with at least one C₁-C₄ alkoxy group.

The term “alkenyl”, as used herein, refers to either a straight chain orbranched-chain hydrocarbon moiety containing at least one double bondand having from 2-12 carbon atoms, preferably 2-6 carbon atoms, morepreferably 2-4 carbon atoms. Such hydrocarbon alkenyl moieties may bemono or polyunsaturated, and may exist in the E or Z configurations. Thecompounds of this invention are meant to include all possible E and Zconfigurations. Examples of mono or polyunsaturated hydrocarbon alkenylmoieties include, but are not limited to, chemical groups such as vinyl,2-propenyl, isopropenyl, crotyl, 2-isopentenyl, butadienyl,2-(butadienyl), 2,4-pentadienyl, 3-(1,4-pentadienyl), and higherhomologs, isomers, or the like.

The term “haloalkenyl” as used herein, designates an alkenyl group asdefined hereinabove substituted with one or more halogen atoms which maybe the same or different.

The term “alkynyl”, as used herein, refers to an alkyl group having oneor more triple carbon-carbon bonds. Alkynyl groups preferably contain 2to 6 carbon atoms. Examples of alkynyl groups include, but are notlimited to, ethynyl, propynyl, butynyl, pentynyl, and the like. In someembodiments, alkynyl groups can be substituted with up to foursubstituent groups, as described hereinabove.

The term “cycloalkyl”, as used herein, refers to a monocyclic, bicyclic,tricyclic, fused, bridged, or spiro saturated carbocyclic moiety of 3-10carbon atoms. Any suitable ring position of the cycloalkyl moiety may becovalently linked to the defined chemical structure. Examples ofcycloalkyl moieties include, but are not limited to, chemical groupssuch as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,norbornyl, adamantyl, spiro[4.5]decanyl, and homologs, isomers, or thelike.

The term “cycloheteroalkyl” as used herein designates a 5- to 7-memberedcycloalkyl ring system containing 1, 2 or 3 heteroatoms, which may bethe same or different, selected from N, O or S, and optionallycontaining one double bond. Exemplary of the cycloheteroalkyl ringsystems included in the term as designated herein are the followingrings wherein X₁ is NR′, O or S, and R′ is H or an optional substituentas defined hereinabove.

The term “aryl”, as used herein, designates an aromatic carbocyclicmoiety of up to 20 carbon atoms, e.g. 6-20 carbon atoms, which may be asingle ring (monocyclic) or multiple rings (bicyclic, up to three rings)fused together or linked covalently. Examples of aryl moieties include,but are not limited to, chemical groups such as phenyl, 1-naphthyl,2-naphthyl, dihydronaphthyl, tetrahydronaphthyl, biphenyl, anthryl,phenanthryl, fluorenyl, indanyl, biphenylenyl, acenaphthenyl,acenaphthylenyl, and the like. In some embodiments “aryl” groups can besubstituted with from 1-5 substituents.

The term “heteroaryl” as used herein designates an aromatic heterocyclicring system, e.g. having from 5-20 ring atoms, which may be a singlering (monocyclic) or multiple rings (bicyclic, up to three rings) fusedtogether or linked covalently. Preferably, heteroaryl is a 5- to6-membered ring. The rings may contain from one to four hetero atomsselected from nitrogen, oxygen, or sulfur, wherein the nitrogen orsulfur atom(s) are optionally oxidized, or the nitrogen atom(s) areoptionally quaternized. Examples of heteroaryl moieties include, but arenot limited to, heterocycles such as furan, thiophene, pyrrole,pyrazole, imidazole, oxazole, isoxazole, thiazole, isothiazole,1H-tetrazole, 1,3,4-oxadiazole, 1H-1,2,4-triazole, 1,3,4-triazole,pyridine, pyrimidine, pyrazine, pyridazine, benzoxazole, benzisoxazole,benzothiazole, benzofuran, benzothiophene, thianthrene, benzimidazole,indole, indazole, quinoline, isoquinoline, quinazoline, quinoxaline,purine, pteridine, 9H-carbazole, α-carboline, or the like.

The term “halogen”, as used herein, designates fluorine, chlorine,bromine, or iodine.

The compounds of the present invention may be converted to salts, inparticular pharmaceutically acceptable salts using art recognizedprocedures. Suitable salts with bases are, for example, metal salts,such as alkali metal or alkaline earth metal salts, for example sodium,potassium or magnesium salts, or salts with ammonia or an organic amine,such as morpholine, thiomorpholine, piperidine, pyrrolidine, a mono-,di- or tri-lower alkylamine, for example ethyl-tert-butyl-, diethyl-,diisopropyl-, triethyl-, tributyl- or dimethylpropylamine, or a mono-,di-, or trihydroxy lower alkylamine, for example mono-, di- ortriethanolamine. Internal salts may furthermore be formed. Salts whichare unsuitable for pharmaceutical uses but which can be employed, forexample, for the isolation or purification of free compounds or theirpharmaceutically acceptable salts, are also included. The term“pharmaceutically acceptable salt”, as used herein, refers to saltsderived form organic and inorganic acids such as, for example, acetic,propionic, lactic, citric, tartaric, succinic, fumaric, maleic, malonic,mandelic, malic, phthalic, hydrochloric, hydrobromic, phosphoric,nitric, sulfuric, methanesulfonic, napthalenesulfonic, benzenesulfonic,toluenesulfonic, camphorsulfonic, and similarly known acceptable acidswhen a compound of this invention contains a basic moiety. Salts mayalso be formed from organic and inorganic bases, preferably alkali metalsalts, for example, sodium, lithium, or potassium, when a compound ofthis invention contains a carboxylate or phenolic moiety, or similarmoiety capable of forming base addition salts.

Compounds of the invention may exist as one or more tautomers. Oneskilled in the art will recognize that compounds of formula I may alsoexist as the tautomer It as shown below.

Tautomers often exist in equilibrium with each other. As these tautomersinterconvert under environmental and physiological conditions, theyprovide the same useful biological effects. The present inventionincludes mixtures of such tautomers as well as the individual tautomers,for example the compounds of Formulas I, It, Ita, Itb and the like.

The compounds of this invention may contain an asymmetric carbon atomand some of the compounds of this invention may contain one or moreasymmetric centers and may thus give rise to optical isomers anddiastereomers. While shown without respect to stereochemistry in FormulaI, the present invention includes such optical isomers anddiastereomers; as well as the racemic and resolved, enantiomericallypure R and S stereoisomers; as well as other mixtures of the R and Sstereoisomers and pharmaceutically acceptable salts thereof. Where astereoisomer is preferred, it may in some embodiments be providedsubstantially free of the corresponding enantiomer. Thus, an enantiomersubstantially free of the corresponding enantiomer refers to a compoundthat is isolated or separated via separation techniques or prepared freeof the corresponding enantiomer. “Substantially free”, as used herein,means that the compound is made up of a significantly greater proportionof one steriosomer, preferably less than about 50%, more preferably lessthan about 75%, and even more preferably less than about 90%.

Preferred compounds of formula I are those compounds wherein R₁ and R₂are H. Another group of preferred compounds are those compounds offormula I wherein R₃ is C₁-C₄alkyl. Also preferred are those compoundsof formula I wherein R₄, R₅ and R₆ are each independently H, halogen,COR₇, OR₁₄, or an alkyl, haloalkyl, alkoxy, haloalkoxy, alkynyl orcycloalkyl group each optionally substituted.

More preferred compounds of the invention are those compounds of formulaI wherein R₁ and R₂ are H and R₃ is methyl. Another group of morepreferred compounds of the invention are those compounds of formula Iwherein R₄ is H, COR₇, OR₁₄ or an alkyl, haloalkyl, alkoxy, haloalkoxy,alkynyl or cycloalkyl group each group optionally substituted; and R₅and R₆ are each independently H or halogen. In one embodiment R₄ isoptionally substituted with one or more groups selected from alkenyl,alkynyl, halo, hydroxy, alkoxy or cycloalkyl. In another embodiment R₄is at the 3-position of the phenyl ring.

A further group of more preferred compounds of the invention are thosecompounds of formula I wherein R₁ and R₂ are H; R₃ is methyl; R₄ is H,COR₇ or an alkyl, haloalkyl, alkoxy, haloalkoxy, alkynyl or cycloalkylgroup each group optionally substituted; R₅ and R₆ are eachindependently H or halogen; and R₄ is at the 3-position of the phenylring.

Preferred compounds of the invention include:

-   (5S)-2-Amino-5-[4-(difluoromethoxy)phenyl]-3-methyl-5-phenyl-3,5-dihydro-4H-imidazol-4-one;-   (5R)-2-Amino-5-[4-(difluoromethoxy)-phenyl]-3-methyl-5-phenyl-3,5-dihydro-4H-imidazol-4-one;-   (5R)-2-amino-5-(3-bromophenyl)-5-[4-(difluoromethoxy)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one;-   (5S)-2-amino-5-(3-bromophenyl)-5-[4-(difluoromethoxy)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one;-   (5R)-2-Amino-5-(3-bromo-4-fluorophenyl)-5-[4-(difluoromethoxy)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one;-   (5S)-2-Amino-5-(3-bromo-4-fluorophenyl)-5-[4-(difluoromethoxy)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one;-   (5R)-2-Amino-5-[4-(difluoromethoxy)phenyl]-3-methyl-5-(3-propylphenyl)-3,5-dihydro-4H-imidazol-4-one;-   (5S)-2-Amino-5-[4-(difluoromethoxy)phenyl]-3-methyl-5-(3-propylphenyl)-3,5-dihydro-4H-imidazol-4-one;-   2-Amino-5-[4-(difluoromethoxy)phenyl]-5-[3-(3-fluoropropyl)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one;-   2-Amino-5-[4-(difluoromethoxy)phenyl]-5-[3-(3,3-difluoropropyl)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one;-   2-Amino-5-[4-(difluoromethoxy)phenyl]-5-[3-(4-fluorobutyl)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one;-   2-Amino-5-[3-(4,4-difluorobutyl)phenyl]-5-[4-(difluoromethoxy)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one;-   2-Amino-5-[4-(difluoromethoxy)phenyl]-5-[3-(2-fluoroethyl)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one;-   2-Amino-5-[3-(2,2-difluoroethyl)phenyl]-5-[4-(difluoromethoxy)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one;-   2-Amino-5-[4-(difluoromethoxy)phenyl]-3-methyl-5-[3-(2,2,2-trifluoroethyl)phenyl]-3,5-dihydro-4H-imidazol-4-one;-   2-Amino-5-[4-(difluoromethoxy)phenyl]-3-methyl-5-[3-(3,3,3-trifluoropropyl)phenyl]-3,5-dihydro-4H-imidazol-4-one;-   2-Amino-5-[4-(difluoromethoxy)phenyl]-3-methyl-5-[3-(4,4,4-trifluorobutyl)phenyl]-3,5-dihydro-4H-imidazol-4-one;-   (5R)-2-amino-5-(3-butylphenyl)-5-[4-(difluoromethoxy)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one;-   (5S)-2-amino-5-(3-butylphenyl)-5-[4-(difluoromethoxy)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one;-   2-Amino-5-[4-(difluoromethoxy)phenyl]-3-methyl-5-(3-pentylphenyl)-3,5-dihydro-4H-imidazol-4-one;-   2-Amino-5-[4-(difluoromethoxy)phenyl]-3-methyl-5-[3-(2-methylbutyl)phenyl]-3,5-dihydro-4H-imidazol-4-one;-   2-Amino-5-(3-but-3-en-1-ylphenyl)-5-[4-(difluoromethoxy)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one;-   2-Amino-5-[3-(cyclopropylmethyl)phenyl]-5-[4-(difluoromethoxy)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one;-   3-(3-{2-Amino-4-[4-(difluoromethoxy)phenyl]-1-methyl-5-oxo-4,5-dihydro-1H-imidazol-4-yl}phenyl)propanenitrile;-   (5R)-2-Amino-5-[4-(difluoromethoxy)phenyl]-3-methyl-5-(3-pent-4-en-1-ylphenyl)-3,5-dihydro-4H-imidazol-4-one;-   (5S)-2-Amino-5-[4-(difluoromethoxy)phenyl]-3-methyl-5-(3-pent-4-en-1-ylphenyl)-3,5-dihydro-4H-imidazol-4-one;-   N-(3-{(4R)-2-Amino-4-[4-(difluoromethoxy)phenyl]-1-methyl-5-oxo-4,5-dihydro-1H-imidazol-4-yl}phenyl)-2-methoxyacetamide;-   N-(3-{(4S)-2-Amino-4-[4-(difluoromethoxy)phenyl]-1-methyl-5-oxo-4,5-dihydro-1H-imidazol-4-yl}phenyl)-2-methoxyacetamide;-   (5S)-2-amino-5-[4-(difluoromethoxy)phenyl]-3-methyl-5-phenyl-3,5-dihydro-4H-imidazol-4-one;-   2-amino-5-[4-(difluoromethoxy)phenyl]-5-[3-(4-hydroxybut-1-yn-1-yl)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one;-   2-amino-5-[4-(difluoromethoxy)phenyl]-5-[3-(4-hydroxybutyl)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one;-   2-amino-5-[4-(difluoromethoxy)phenyl]-5-[3-(5-fluoropentyl)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one;-   2-amino-5-[4-(difluoromethoxy)phenyl]-5-[3-(4-fluorobutyl)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one;-   2-amino-5-[4-(difluoromethoxy)phenyl]-5-[3-(6-fluorohexyl)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one;-   2-amino-5-[4-(difluoromethoxy)phenyl]-5-[3-(4-methoxybutyl)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one;-   2-amino-5-[4-(difluoromethoxy)phenyl]-5-{3-[(1Z)-3-methoxyprop-1-en-1-yl]phenyl}-3-methyl-3,5-dihydro-4H-imidazol-4-one;-   2-amino-5-[4-(difluoromethoxy)phenyl]-5-[3-(3-methoxypropyl)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one;-   2-amino-5-[3-(4,4-difluorobutyl)phenyl]-5-[4-(difluoromethoxy)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one;-   3-{2-amino-4-[4-(difluoromethoxy)phenyl]-1-methyl-5-oxo-4,5-dihydro-1H-imidazol-4-yl}-N-propylbenzamide;-   (1E)-3-chloroprop-1-enyl 2,5-dichlorophenyl sulfone;-   2-amino-5-[4-(difluoromethoxy)phenyl]-5-{3-[(2-fluoroethoxy)methyl]phenyl}-3-methyl-3,5-dihydro-4H-imidazol-4-one;-   2-amino-5-[4-(difluoromethoxy)phenyl]-3-methyl-5-{3-[(3,3,3-trifluoropropoxy)methyl]phenyl}-3,5-dihydro-4H-imidazol-4-one;-   2-amino-5-[4-(difluoromethoxy)phenyl]-5-[3-(methoxymethyl)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one;-   2-amino-5-[3-(butoxymethyl)phenyl]-5-[4-(difluoromethoxy)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one;-   2-amino-5-{3-[(cyclopropylmethoxy)methyl]phenyl}-5-[4-(difluoromethoxy)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one;-   2-amino-5-[4-(difluoromethoxy)phenyl]-5-[3-(ethoxymethyl)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one;-   2-amino-5-[4-(difluoromethoxy)phenyl]-3-methyl-5-[3-(propoxymethyl)phenyl]-3,5-dihydro-4H-imidazol-4-one;-   2-amino-5-[4-(difluoromethoxy)phenyl]-5-(3-{[2-fluoro-1-(fluoromethyl)ethoxy]methyl}phenyl)-3-methyl-3,5-dihydro-4H-imidazol-4-one;-   2-amino-5-[4-(difluoromethoxy)phenyl]-3-methyl-5-{3-[(2,2,2-trifluoroethoxy)methyl]phenyl}-3,5-dihydro-4H-imidazol-4-one;-   2-amino-5-[4-(difluoromethoxy)phenyl]-3-methyl-5-{3-[(2,2,3,3-tetrafluoropropoxy)methyl]phenyl}-3,5-dihydro-4H-imidazol-4-one;-   4-[4-(difluoromethoxy)phenyl]-4-[3-(3-methoxyprop-1-yn-1-yl)phenyl]-1-methyl-4,5-dihydro-1H-imidazol-2-amine;-   2-amino-5-[3-(1,4-difluorobutyl)phenyl]-5-[4-(difluoromethoxy)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one;-   2-amino-5-[4-(difluoromethoxy)phenyl]-5-[3-(3-fluorobut-3-en-1-yl)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one;-   2-amino-5-[3-(4,4-difluorobut-3-en-1-yl)phenyl]-5-[4-(difluoromethoxy)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one;-   2-amino-5-[4-(difluoromethoxy)phenyl]-3-methyl-5-[3-(4,4,4-trifluorobutyl)phenyl]-3,5-dihydro-4H-imidazol-4-one;-   5-(3-{2-amino-4-[4-(difluoromethoxy)phenyl]-1-methyl-5-oxo-4,5-dihydro-1H-imidazol-4-yl}phenyl)pentanenitrile;-   4-(3-{2-amino-4-[4-(difluoromethoxy)phenyl]-1-methyl-5-oxo-4,5-dihydro-1H-imidazol-4-yl}phenyl)butanenitrile;-   2-amino-5-{3-[(1E)-4,4-difluorobut-1-en-1-yl]phenyl}-5-[4-(difluoromethoxy)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one;-   2-amino-5-[4-(difluoromethoxy)phenyl]-5-[3-(3-hydroxyhex4-yn-1-yl)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one;-   2-amino-5-[4-(difluoromethoxy)phenyl]-5-{3-[(1E)-6-methoxyhex-1-en-1-yl]phenyl}-3-methyl-3,5-dihydro-4H-imidazol-4-one;-   2-amino-5-[4-(difluoromethoxy)phenyl]-5-{3-[(1E)-5-methoxypent-1-en-1-yl]phenyl}-3-methyl-3,5-dihydro-4H-imidazol-4-one;-   2-amino-5-[4-(difluoromethoxy)phenyl]-5-{3-[2-(methoxymethyl)cyclopropyl]phenyl}-3-methyl-3,5-dihydro-4H-imidazol-4-one;-   2-amino-5-[4-(difluoromethoxy)phenyl]-5-{3-[(1E)-5-hydroxypent-1-en-1-yl}phenyl}-3-methyl-3,5-dihydro-4H-imidazol-4-one;-   2-amino-5-[4-(difluoromethoxy)phenyl]-5-{3-[(1E)-3-methoxyprop-1-en-1-yl]phenyl}-3-methyl-3,5-dihydro-4H-imidazol-4-one;-   2-amino-5-[4-(difluoromethoxy)phenyl]-5-{3-[(1E)-4-methoxybut-1-en-1-yl]phenyl}-3-methyl-3,5-dihydro-4H-imidazol-4-one;-   2-amino-5-[4-(difluoromethoxy)phenyl]-5-{3-[(1E)-4-hydroxybut-1-en-1-yl]phenyl}-3-methyl-3,5-dihydro-4H-imidazol-4-one;-   2-amino-5-[4-(difluoromethoxy)phenyl]-5-{3-[2-(2-methoxyethyl)cyclopropyl]phenyl}-3-methyl-3,5-dihydro-4H-imidazol-4-one;-   2-amino-5-[4-(difluoromethoxy)phenyl]-5-{3-[(1E)-4-fluorobut-1-en-1-yl]phenyl}-3-methyl-3,5-dihydro-4H-imidazol-4-one;-   2-amino-5-[4-(difluoromethoxy)phenyl]-5-{3-[(1E)-5-fluoropent-1-en-1-yl]phenyl}-3-methyl-3,5-dihydro-4H-imidazol-4-one;-   5-(3-acetylphenyl)-2-amino-5-[4-(difluoromethoxy)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one;-   2-amino-5-[4-(difluoromethoxy)phenyl]-5-{4-fluoro-3-[(1E)-4-fluorobut-1-en-1-yl]phenyl}-3-methyl-3,5-dihydro-4H-imidazol-4-one;-   2-amino-5-[4-(difluoromethoxy)phenyl]-5-[3-(3-fluoroprop-1-yn-1-yl)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one;-   2-amino-5-[4-(difluoromethoxy)phenyl]-5-(3-hydroxyphenyl)-3-methyl-3,5-dihydro-4H-imidazol-4-one;-   2-amino-5-[4-(difluoromethoxy)phenyl]-5-[3-(3-fluoropropoxy)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one;-   2-amino-5-[3-(cyclopropylmethoxy)phenyl]-5-[4-(difluoromethoxy)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one;-   2-amino-5-[4-(difluoromethoxy)phenyl]-3-methyl-5-[3-(4,4,4-trifluorobutoxy)phenyl]-3,5-dihydro-4H-imidazol-4-one;-   2-amino-5-[3-(2,2-difluoroethoxy)phenyl]-5-[4-(difluoromethoxy)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one;-   2-amino-5-[4-(difluoromethoxy)phenyl]-5-[3-(4-fluorobutoxy)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one;-   2-amino-5-[4-(difluoromethoxy)phenyl]-3-methyl-5-[3-(3-phenoxypropoxy)phenyl]-3,5-dihydro-4H-imidazol-4-one;-   4-(3-{2-amino-4-[4-(difluoromethoxy)phenyl]-1-methyl-5-oxo-4,5-dihydro-1H-imidazol-4-yl}phenoxy)butanenitrile;-   2-amino-5-[4-(difluoromethoxy)phenyl]-5-[4-fluoro-3-(3-fluoropropoxy)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one;-   2-amino-5-[3-(but-2-yn-1-yloxy)-4-fluorophenyl]-5-[4-(difluoromethoxy)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one;-   2-amino-5-[4-(difluoromethoxy)phenyl]-5-[4-fluoro-3-(4-fluorobutoxy)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one;-   2-amino-5-[3-(2,2-difluoroethoxy)-4-fluorophenyl]-5-[4-(difluoromethoxy)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one;-   (5R)-2-amino-5-[4-(difluoromethoxy)phenyl]-5-[4-fluoro-3-(3-fluoropropoxy)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one;-   (5S)-2-amino-5-[4-(difluoromethoxy)phenyl]-5-[4-fluoro-3-(3-fluoropropoxy)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one;-   2-amino-5-{3-[(4,4-difluorobut-3-en-1-yl)oxy]phenyl}-5-[4-(difluoromethoxy)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one;-   (5S)-2-amino-5-[3-(2,2-difluoroethoxy)-4-fluorophenyl]-5-[4-(difluoromethoxy)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one;-   (5R)-2-amino-5-[3-(2,2-difluoromethoxy)-4-fluorophenyl]-5-[4-(difluoromethoxy)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one;-   2-amino-5-[4-(difluoromethoxy)phenyl]-5-[3-(2-fluoroethyl)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-one;-   2-amino-5-[4-(difluoromethoxy)phenyl]-5-[3-(5-fluoropentanoyl)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one;-   2-amino-5-[4-(difluoromethoxy)phenyl]-5-[3-(4-fluorobutanoyl)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one;-   2-amino-5-[3-(but-3-en-1-yloxy)phenyl]-5-[4-(difluoromethoxy)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one;-   2-amino-5-[3-(but-3-en-1-yloxy)-4-fluorophenyl]-5-[4-(difluoromethoxy)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one;-   (5R)-2-amino-5-[3-(but-3-en-1-yloxy)phenyl]-5-[4-(difluoromethoxy)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one;-   (5S)-2-amino-5-[3-(but-3-en-1-yloxy)phenyl]-5-[4-(difluoromethoxy)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one;-   2-amino-5-{3-[(4,4-difluorobut-3-en-1-yl)oxy]-4-fluorophenyl}-5-[4-(difluoromethoxy)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one;-   2-amino-5-[4-(difluoromethoxy)phenyl]-5-(4-fluoro-3-pent-4-en-1-ylphenyl)-3-methyl-3,5-dihydro-4H-imidazol-4-one;-   2-amino-5-(3-but-3-en-1-yl-4-fluorophenyl)-5-[4-(difluoromethoxy)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one;-   3-{2-amino-4-[4-(difluoromethoxy)phenyl]-1-methyl-5-oxo-4,5-dihydro-1H-imidazol-4-yl}benzaldehyde;-   2-amino-5-[4-(difluoromethoxy)phenyl]-5-[3-(1-hydroxybut-2-yn-1-yl)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one;-   2-amino-5-[4-(difluoromethoxy)phenyl]-5-[3-(1,4-dihydroxybut-2-yn-1-yl)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one;-   (5R)-2-amino-5-[3-(difluoromethoxy)phenyl]-5-[4-(difluoromethoxy)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one;-   2-amino-5-[4-(difluoromethoxy)phenyl]-5-[3-(2,2-dimethyl-3-oxocyclobutyl)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one;-   2-amino-5-[4-(difluoromethoxy)phenyl]-3-methyl-5-[3-(3-oxocyclobutyl)phenyl]-3,5-dihydro-4H-imidazol-4-one;-   2-amino-5-[4-(difluoromethoxy)phenyl]-5-[3-(3-hydroxycyclobutyl)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one;-   methyl    [3-(3-{2-amino-4-[4-(difluoromethoxy)phenyl]-1-methyl-5-oxo-4,5-dihydro-1H-imidazol-4-yl}phenyl)cyclobutyl]acetate;-   methyl    (3-(3-{2-amino-4-[4-(difluoromethoxy)phenyl]-1-methyl-5-oxo-4,5-dihydro-1H-imidazol-4-yl}phenyl)cyclobutylidene]acetate;    or a tautomer thereof, a stereoisomer thereof or a pharmaceutically    acceptable salt thereof.

More preferred compounds of the invention include:

-   (5S)-2-amino-5-[4-(difluoromethoxy)phenyl]-3-methyl-5-phenyl-3,5-dihydro-4H-imidazol-4-one;-   (5R)-2-amino-5-[4-(difluoromethoxy)phenyl]-3-methyl-5-(3-pent-4-en-1-ylphenyl)-3,5-dihydro-4H-imidazol-4-one;-   (5R)-2-amino-5-[4-(difluoromethoxy)phenyl]-3-methyl-5-(3-prop-1-yn-1-ylphenyl)-3,5-dihydro-4H-imidazol-4-one;-   (5R)-2-amino-5-[4-(difluoromethoxy)phenyl]-3-methyl-5-(3-pent-1-yn-1-ylphenyl)-3,5-dihydro-4H-imidazol-4-one;-   (5R)-2-amino-5-[4-(difluoromethoxy)phenyl]-3-methyl-5-[3-(3-methylbut-1-yn-1-yl)phenyl]-3,5-dihydro-4H-imidazol-4-one;-   (5R)-2-amino-5-[4-(difluoromethoxy)phenyl]-5-[3-(3-methoxyprop-1-yn-1-yl)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one;-   (5R)-2-amino-5-[4-(difluoromethoxy)phenyl]-5-[3-(4-methoxybut-1-yn-1-yl)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one;-   (5R)-2-amino-5-[4-(difluoromethoxy)phenyl]-5-[3-(5-fluoropent-1-yn-1-yl)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one;-   (5R)-2-amino-5-[4-(difluoromethoxy)phenyl]-5-{3-[(3S)-3-hydroxybut-1-yn-1-yl]phenyl}-3-methyl-3,5-dihydro-4H-imidazol-4-one;-   (5R)-2-amino-5-[4-(difluoromethoxy)phenyl]-5-[4-fluoro-3-(3-methoxyprop-1-yn-1-yl)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one;-   (5R)-2-amino-5-[4-(difluoromethoxy)phenyl]-5-[4-fluoro-3-(4-methoxybut-1-yn-1-yl)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one;-   (5R)-2-amino-5-[4-(difluoromethoxy)phenyl]-5-[4-fluoro-3-(3-fluoropropoxy)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one;-   (5R)-2-amino-5-[3-(2,2-difluoroethoxy)-4-fluorophenyl]-5-[4-(difluoromethoxy)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one;-   (5R)-2-amino-5-{3-[(4,4-difluorobut-3-en-1-yl)oxy]phenyl}-5-[4-(difluoromethoxy)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one;    or a tautomer thereof, a stereoisomer thereof or a pharmaceutically    acceptable salt thereof.

Compounds of formula I may be prepared using conventional syntheticmethods and, if required, standard separation or isolation techniques.For example, compounds of formula I may be prepared by reacting adiketone of formula II with an aminoguanidine derivative of formula IIIin the presence of a base such as a metal carbonate to give the desiredformula I compound. The reaction is shown below in flow diagram I.

Flow Diagram I

Diketone compounds of formula II may be prepared by reacting an alkyneof formula IV with an oxidizing agent such as Pd(II)Cl₂/DMSO,N-bromosuccinimide/DMSO, ozone, sodium periodate with ruthenium (IV)oxide hydrate, sulfur trioxide, KMnO₄, I₂/DMSO, or combinations thereof,preferable KMnO₄ and I₂/DMSO. The reaction is shown in flow diagram II.

Flow Diagram II

Alkyne compounds of formula IV may be prepared by reacting anethynylbenzene compound of formula V with4-(difluoromethoxy)-1-iodobenzene in the presence of a Pd catalyst, suchas dichlorobis(triphenylphosphine)palladium (II), and Cul to give thedesired phenylethynylbenzene compound of formula IV. The reaction isshown in flow diagram III.

Flow Diagram III

Advantageously, the compounds of formula I act as BACE inhibitors forthe treatment of β-amyloid deposits and neurofibrillary tanglesassociated with such diseases as Alzheimer's disease, Trisomy 21 (Down'sSyndrome), Hereditary Cerebral Hemorrhage with Amyloidosis of theDutch-type (HCHWA-D), and other neurodegenerative disorders.Accordingly, the present invention provides methods for modulating BACEand treating, preventing, or ameliorating β-amyloid deposits andneurofibrillary tangles associated with diseases and disorders such asAlzheimer's disease, Trisomy 21 (Down's Syndrome), Hereditary CerebralHemorrhage with Amyloidosis of the Dutch-type (HCHWA-D), or otherneurodegenerative disorders. Such methods include providing a patientsuffering from or being susceptible to a disease or injury associatedwith excessive BACE activity an effective amount of a compound offormula I. Also according to the present invention there is provided amethod of treating Alzheimer's disease and related senile dementia's inhumans or other mammals which comprises administering to a human orother mammal an effective amount of a compound of the present invention.

The present invention also provides a method for the treatment of adisorder related to or associated with excessive BACE activity in apatient in need thereof which comprises providing said patient atherapeutically effective amount of at least one compound of formula I.Representative disorders include Alzheimer's disease, cognitiveimpairment, Down's Syndrome, HCHWA-D, cognitive decline, seniledementia, cerebral amyloid angiopathy, degenerative dementia, or otherneurodegenerative disorders. Certain of these diseases are characterizedby production of β-amyloid deposits or neurofibrillary tangles.

The present invention also provides a method for inhibiting the activityof BACE, comprising administering to a patient or contacting a receptorthereof with an effective amount of at least one compound of formula I.Certain methods further comprise determining BACE activity, eitherbefore or after said contacting step.

The present invention also provides a method of ameliorating β-amyloiddeposits or neurofibrillary tangles in a mammal which comprisesproviding said mammal an effective amount of at least one compound offormula I.

Also provided are methods of ameliorating symptoms of Alzheimer'sdisease, cognitive impairment, Down's Syndrome, HCHWA-D, cognitivedecline, senile dementia, cerebral amyloid angiopathy, degenerativedementia, or other neurodegenerative disorders in a mammal whichcomprises providing said mammal an effective amount of at least onecompound of formula I.

Further methods prevent Alzheimer's disease, cognitive impairment,Down's Syndrome, HCHWA-D, cognitive decline, senile dementia, cerebralamyloid angiopathy, degenerative dementia, or other neurodegenerativedisorders in a mammal that is known to suffer from or suspected to be atrisk of suffering from such diseases. These methods comprise providingsaid mammal an effective amount of at least one compound of formula I.

As used in accordance with this invention, the term “providing,” withrespect to providing a compound or substance covered by this invention,means either directly administering such a compound or substance, oradministering a prodrug, derivative, or analog which will form theeffective amount of the compound or substance within the body. Thisinvention also covers providing the compounds of this invention to treatthe disease states disclosed herein that the compounds are useful fortreating.

The term “patient”, as used herein, refers to a mammal, preferably ahuman.

The terms “administer”, “administering”, or “administration”, as usedherein, refer to either directly administering a compound or compositionto a patient, or administering a prodrug derivative or analog of thecompound to the patient, which will form an equivalent amount of theactive compound or substance within the patient's body.

The terms “effective amount”, “therapeutically effective amount” and“effective dosage” as used herein, refer to the amount of a compoundthat, when administered to a patient, is effective to at least partiallyameliorate (and, in preferred embodiments, cure) a condition from whichthe patient is suspected to suffer.

It is understood that the effective dosage of the active compounds ofthis invention may vary depending upon the particular compound utilized,the mode of administration, the condition, and severity thereof, of thecondition being treated, as well as the various physical factors relatedto the individual being treated. For treating Alzheimer's disease andother related senile dementia's, generally, satisfactory results may beobtained when the compounds of this invention are administered to theindividual in need at a daily dosage of from about 0.1 mg to about 1 mgper kilogram of body weight, preferably administered in divided dosestwo to six times per day, or in a sustained release form. For most largemammals, the total daily dosage is from about 3.5 mg to about 140 mgpreferably from about 3.5 to about 5 mg. In the case of a 70 kg humanadult, the total daily dose will generally be from about 7 mg to about70 mg and may be adjusted to provide the optimal therapeutic result.This regimen may be adjusted to provide the optimal therapeuticresponse.

In one aspect, the present invention is directed to compositionscomprising one or more compounds of formula I and one or morepharmaceutically acceptable carriers.

The present invention also comprises pharmaceutical compositionscomprising compounds of the above-described formula I and apharmaceutically acceptable carrier.

The term “carrier”, as used herein, shall encompass carriers,excipients, and diluents. Examples of carriers are well known to thoseskilled in the art and are prepared in accordance with acceptablepharmaceutical procedures, such as, for example, those described inRemington's Pharmaceutical Sciences, 17th edition, ed. Alfonoso R.Gennaro, Mack Publishing Company, Easton, Pa. (1985), which isincorporated herein by reference in its entirety. Pharmaceuticallyacceptable carriers are those that are compatible with the otheringredients in the formulation and biologically acceptable.

The compounds of this invention may be administered orally orparenterally, neat or in combination with conventional pharmaceuticalcarriers. Applicable solid carriers can include one or more substanceswhich may also act as flavoring agents, lubricants, solubilizers,suspending agents, fillers, glidants, compression aids, binders ortablet-disintegrating agents or encapsulating materials. They areformulated in conventional manner, for example, in a manner similar tothat used for known antihypertensive agents, diuretics and β-blockingagents. Oral formulations containing the active compounds of thisinvention may comprise any conventionally used oral forms, includingtablets, capsules, buccal forms, troches, lozenges and oral liquids,suspensions or solutions. In powders, the carrier is a finely dividedsolid, which is an admixture with the finely divided active ingredient.In tablets, the active ingredient is mixed with a carrier having thenecessary compression properties in suitable proportions and compactedin the shape and size desired. The powders and tablets preferablycontain up to 99% of the active ingredient.

Capsules may contain mixtures of the active compound(s) with inertfillers and/or diluents such as the pharmaceutically acceptable starches(e.g. corn, potato or tapioca starch), sugars, artificial sweeteningagents, powdered celluloses, such as crystalline and microcrystallinecelluloses, flours, gelatins, gums, etc.

Useful tablet formulations may be made by conventional compression, wetgranulation or dry granulation methods and utilize pharmaceuticallyacceptable diluents, binding agents, lubricants, disintegrants, surfacemodifying agents (including surfactants), suspending or stabilizingagents, including, but not limited to, magnesium stearate, stearic acid,sodium lauryl sulfate, talc, sugars, lactose, dextrin, starch, gelatin,cellulose, methyl cellulose, microcrystalline cellulose, sodiumcarboxymethyl cellulose, carboxymethylcellulose calcium,polyvinylpyrrolidine, alginic acid, acacia gum, xanthan gum, sodiumcitrate, complex silicates, calcium carbonate, glycine, sucrose,sorbitol, dicalcium phosphate, calcium sulfate, lactose, kaolin,mannitol, sodium chloride, low melting waxes and ion exchange resins.Preferred surface modifying agents include nonionic and anionic surfacemodifying agents. Representative examples of surface modifying agentsinclude, but are not limited to, poloxamer 188, benzalkonium chloride,calcium stearate, cetostearl alcohol, cetomacrogol emulsifying wax,sorbitan esters, colliodol silicon dioxide, phosphates, sodiumdodecylsulfate, magnesium aluminum silicate, and triethanolamine. Oralformulations herein may utilize standard delay or time releaseformulations to alter the absorption of the active compound(s). The oralformulation may also consist of administering the active ingredient inwater or fruit juice, containing appropriate solubilizers oremulisifiers as needed.

Liquid carriers may be used in preparing solutions, suspensions,emulsions, syrups and elixirs. The active ingredient of this inventioncan be dissolved or suspended in a pharmaceutically acceptable liquidcarrier such as water, an organic solvent, a mixture of both orpharmaceutically acceptable oils or fat. The liquid carrier can containother suitable pharmaceutical additives such as solubilizers,emulsifiers, buffers, preservatives, sweeteners, flavoring agents,suspending agents, thickening agents, colors, viscosity regulators,stabilizers or osmo-regulators. Suitable examples of liquid carriers fororal and parenteral administration include water (particularlycontaining additives as above, e.g. cellulose derivatives, preferablysodium carboxymethyl cellulose solution), alcohols (including monohydricalcohols and polyhydric alcohols, e.g. glycols) and their derivatives,and oils (e.g. fractionated coconut oil and arachis oil). For parenteraladministration the carrier can also be an oily ester such as ethyloleate and isopropyl myristate. Sterile liquid carriers are used insterile liquid form compositions for parenteral administration. Theliquid carrier for pressurized compositions can be halogenatedhydrocarbon or other pharmaceutically acceptable propellant.

Liquid pharmaceutical compositions, which are sterile solutions orsuspensions, can be utilized by, for example, intramuscular,intraperitoneal or subcutaneous injection. Sterile solutions can also beadministered intravenously. Compositions for oral administration may bein either liquid or solid form.

Preferably the pharmaceutical composition is in unit dosage form, e.g.as tablets, capsules, powders, solutions, suspensions, emulsions,granules, or suppositories. In such form, the composition is sub-dividedin unit dose containing appropriate quantities of the active ingredient;the unit dosage forms can be packaged compositions, for example,packeted powders, vials, ampoules, prefilled syringes or sachetscontaining liquids. The unit dosage form can be, for example, a capsuleor tablet itself, or it can be the appropriate number of any suchcompositions in package form. Such unit dosage form may contain fromabout 1 mg/kg to about 250 mg/kg, and may given in a single dose or intwo or more divided doses. Such doses may be administered in any manneruseful in directing the active compounds herein to the recipient'sbloodstream, including orally, via implants, parenterally (includingintravenous, intraperitoneal and subcutaneous injections), rectally,vaginally, and transdermally. Such administrations may be carried outusing the present compounds, or pharmaceutically acceptable saltsthereof, in lotions, creams, foams, patches, suspensions, solutions, andsuppositories (rectal and vaginal).

When administered for the treatment or inhibition of a particulardisease state or disorder, it is understood that the effective dosagemay vary depending upon the particular compound utilized, the mode ofadministration, the condition, and severity thereof, of the conditionbeing treated, as well as the various physical factors related to theindividual being treated. In therapeutic application, compounds of thepresent invention are provided to a patient already suffering from adisease in an amount sufficient to cure or at least partially amelioratethe symptoms of the disease and its complications. An amount adequate toaccomplish this is defined as a “therapeutically effective amount”. Thedosage to be used in the treatment of a specific case must besubjectively determined by the attending physician. The variablesinvolved include the specific condition and the size, age and responsepattern of the patient.

In some cases it may be desirable to administer the compounds directlyto the airways in the form of an aerosol. For administration byintranasal or intrabrochial inhalation, the compounds of this inventionmay be formulated into an aqueous or partially aqueous solution.

The compounds of this invention may be administered parenterally orintraperitoneally. Solutions or suspensions of these active compounds asa free base or pharmaceutically acceptable salt may be prepared in watersuitably mixed with a surfactant such as hydroxyl-propylcellulose.Dispersions may also be prepared in glycerol, liquid polyethyleneglycols and mixtures thereof in oils. Under ordinary conditions ofstorage and use, these preparations contain a preservative to inhibitthe growth of microorganisms.

The pharmaceutical forms suitable for injectable use include sterileaqueous solutions or dispersions and sterile powders for theextemporaneous preparation of sterile injectable solutions ordispersions. In all cases, the form must be sterile and must be fluid tothe extent that easy syringability exists. It must be stable under theconditions of manufacture and storage and must be preserved against thecontaminating action of microorganisms such as bacteria and fungi. Thecarrier can be a solvent or dispersion medium containing, for example,water, ethanol, polyol (e.g., glycerol, propylene glycol and liquidpolyethylene glycol), suitable mixtures thereof, and vegetable oils.

The compounds of this invention can be administered transdermallythrough the use of a transdermal patch. For the purposes of thisdisclosure, thransdermal administrations are understood to include alladministrations across the surface of the body and the inner linings ofbodily passages including epithelial and mucosal tissues. Suchadministrations may be carried out using the present compounds, orpharmaceutically acceptable salts thereof, in lotions, creams, foams,patches, suspensions, solutions, and suppositories (rectal and vaginal).

Transdermal administration may be accomplished through the use of atransdermal patch containing the active compound and a carrier that isinert to the active compound, is non-toxic to the skin, and allowsdelivery of the agent for systemic absorption into the blood stream viathe skin. The carrier may take any number of forms such as creams andointments, pastes, gels and occlusive devices. The creams and ointmentsmay be viscous liquid or semisolid emulsions of either the oil-in-wateror water-in-oil type. Pastes comprised of absorptive powders dispersedin petroleum or hydrophilic petroleum containing the active ingredientmay also be suitable. A variety of occlusive devices may be used torelease the active ingredient into the blood stream, such as asemi-permeable membrane covering a reservoir containing the activeingredient with or without a carrier, or a matrix containing the activeingredient. Other occlusive devices are known in the literature.

The compounds of this invention may be administered rectally orvaginally in the form of a conventional suppository. Suppositoryformulations may be made from traditional materials, including cocoabutter, with or without the addition of waxes to alter the suppository'smelting point, and glycerin. Water soluble suppository bases, such aspolyethylene glycols of various molecular weights, may also be used.

In certain embodiments, the present invention is directed to prodrugs.Various forms of prodrugs are known in the art, for example, asdiscussed in, for example, Bundgaard, (ed.), Design of Prodrugs,Elsevier (1985); Widder, et al. (ed.), Methods in Enzymology, vol. 4,Academic Press (1985); Krogsgaard-Larsen, et al. (ed.), “Design andApplication of Prodrugs”, Textbook of Drug Design and Development,Chapter 5, 113-191 (1991), Bundgaard, et al., Journal of Drug Deliverreviews, 8:1-38 (1992), Bundgaard, J. of Pharmaceutical Sciences, 77:285et seq. (1988); and Higuchi and Stella (eds.) Prodrugs as Novel DrugDelivery Systems, American Chemical Society (1975), each of which isincorporated by reference in its entirety.

It is understood that the dosage, regimen and mode of administration ofthese compounds will vary according to the malady and the individualbeing treated and will be subject to the judgment of the medicalpractitioner involved. It is preferred that the administration of one ormore of the compounds herein begin at a low dose and be increased untilthe desired effects are achieved.

For a more clear understanding, and in order to illustrate the inventionmore clearly, specific examples thereof are set forth hereinbelow. Thefollowing examples are merely illustrative and are not to be understoodas limiting the scope and underlying principles of the invention in anyway.

Unless otherwise stated, all parts are parts by weight. The terms TEA,DMSO and DMF designate triethyl amine, dimethyl sulfoxide andN,N-dimethylformamide, respectively. The terms EtOAc and THF designateethyl acetate and tetrahydrofuran, respectively. The term NMR designatesproton nuclear magnetic resonance and the term MS designates massspectroscopy with (+) referring to the positive mode which generallygives a M+1 (or M+H) absorption where M=the molecular mass. Allcompounds are analyzed at least by MS and NMR.

In the chemical drawings, the term Ph represents phenyl.

Proton nuclear magnetic resonance spectra were obtained on a BrukerAVANCE 300 spectrometer at 300 MHz or VARIAN 400 spectrometer at 400MHz. Spectra are given in ppm (δ) and coupling constants, J values, arereported in Hertz. Tetramethylsilane was used as an internal referencestandard. Mass spectra were obtained on a Perkin Elmer Sciex 100.

EXAMPLE 1 Preparation of(5S)-2-Amino-5-[4-(difluoromethoxy)phenyl]-3-methyl-5-phenyl-3,5-dihydro-4H-imidazol-4-one[A] and(5R)-2-Amino-5-[4-(difluoromethoxy)-phenyl]-3-methyl-5-phenyl-3,5-dihydro-4H-imidazol-4-one[B]

Step a) 1-(Difluoromethoxy)-4-(phenylethynyl)benzene

Into a mixture of ethynylbenzene (1.9 g, 18.5 mmol),1-(difluoromethoxy)-4-iodobenzene (5 g, 18.5 mmol),N,N-dimethylformamide (35 mL), and triethylamine (12.8 mL, 92.6 mmol)was introduced anhydrous argon for 5 minutes. Then, copper(I) iodide(1.85 mmol, 351 mg) and dichlorobis(triphenylphosphine)palladium(II)(1.11, 0.71 g) were added into the mixture and the new mixture wasstirred at 60° C. for 3 hours. The mixture cooled to room temperature,poured into water and extracted with ethyl ether. The organic extractswere dried over MgSO₄. Evaporation and purification on silica gel (ISCO)using hexanes/EtOAc (100/1) as the eluting solvent, gave1-(difluoromethoxy)-4-(phenylethynyl)benzene as a clear oil (3.45 g, 76%yield). MS m/e M⁺ 244; ¹H NMR (400 MHz, DMSO-d₆)

7.2 (d, J=8.78 Hz, 2H), 7.28-7.45 (m, 4H), 7.5-7.55 (m, 2H), 7.6 (d,J=7.78 Hz, 2H).

Step b) 1-[4-(Difluoromethoxy)phenyl]-2-phenylethane-1,2-dione

Into a mixture of 1-(difluoromethoxy)-4-(phenylethynyl)benzene (2.85 g,11.68 mmol) and dimethylsulfoxide (40 mL) was introduced anhydrous argongas for 5 minutes. Then, bis(acetonitrile)dichloropalladium(II) (1.16,0.3 g) was added into the mixture and the new mixture was stirred at145° C. for 20 hours. The mixture cooled to room temperature, pouredinto water and extracted with EtOAc. The organic extracts were driedover MgSO₄. Evaporation and purification on silica gel (ISCO) usinghexanes/EtOAc (30/1) as the eluting solvent gave1-[4-(difluoromethoxy)phenyl]-2-phenylethane-1,2-dione as a clear oil(2.92 g, 91% yield). MS m/e M⁺ 276; ¹H NMR (400 MHz, DMSO-d₆)

7.2 (d, J=8.78 Hz, 2H), 7.6 (m, 3H), 7.75 (t J=8.54 Hz, 1H), 7.88 (d,J=8.54 Hz, 2H), 7.98 (d, J=8.78 Hz, 2H).

Step c)2-Amino-5-[4-(difluoromethoxy)phenyl]-3-methyl-5-phenyl-3,5-dihydro-4H-imidazol-4-one

Into a mixture of 1-[4-(difluoromethoxy)phenyl]-2-phenylethane-1,2-dione(3.7 g, 13.4 mmol), dioxane (180 mL) and EtOH (240 mL) were added1-methylguanidine hydrochloride (6.6 g, 60.3 mmol), and a solution ofNa₂CO₃ (6.4 g, 60.3 mmol) in H₂O (20 mL). The new mixture was stirred at95° C. for 3 hours. Then, the volatiles were removed under vacuum andthe residue was taken in water and extracted with EtOAc. The organicextracts were dried over MgSO₄. Evaporation and purification on silicagel (ISCO) using MeOH/EtOAc (1/20) as the eluting solvent gave2-amino-5-[4-(difluoromethoxy)phenyl]-3-methyl-5-phenyl-3,5-dihydro-4H-imidazol-4-oneas a white solid (3.65 g, 94% yield). MS m/e (M+H)⁺ 332; ¹H NMR (400MHz, DMSO-d₆)

2.93 (s, 3H), 6.61 (brs, 2H), 7.1 (d, J=8.54 Hz, 2H), 7.15-7.31 (m, 4H),7.38 (m, 2H), 7.42 (d, J=8.54 Hz, 2H).

Step d)(5S)-2-Amino-5-[4-(difluoromethoxy)phenyl]-3-methyl-5-phenyl-3,5-dihydro-4H-imidazol-4-one[A] and(5R)-2-Amino-5-[4-(difluoromethoxy)phenyl]-3-methyl-5-phenyl-3,5-dihydro-4H-imidazol-4-one[B]

A racemic mixture of2-amino-5-[4-(difluoromethoxy)phenyl]-3-methyl-5-phenyl-3,5-dihydro-4H-imidazol-4-onewas separated by chiral chromatography technique (Chiralcel OJ, 0.46×10cm, using 15% ethanol in 85% hexane and diethylamine as the mobilephase) to produce the two enantiomers as white solids; [A](5S)-2-amino-5-[4-(difluoromethoxy)phenyl]-3-methyl-5-phenyl-3,5-dihydro-4H-imidazol-4-one,MS m/e (M+H)⁺ 332; ¹H NMR (400 MHz, DMSO-d₆)

2.93 (s, 3H), 6.61 (brs, 2H), 7.1 (d, J=8.54 Hz, 2H), 7.15-7.31 (m, 4H),7.38 (m, 2H), 7.42 (d, J=8.54 Hz, 2H); [a]₂₅=+20 (C=1% in MeOH), and [B](5R)-2-amino-5-[4-(difluoromethoxy)phenyl]-3-methyl-5-phenyl-3,5-dihydro-4H-imidazol-4-one,MS m/e (M+H)⁺ 332; ¹H NMR (400 MHz, DMSO-d₆)

2.93 (s, 3H), 6.61 (brs, 2H), 7.1 (d, J=8.54 Hz, 2H), 7.15-7.31 (m, 4H),7.38 (m, 2H), 7.42 (d, J=8.54 Hz, 2H); [a]₂₅=−22 (C=1% in MeOH).

EXAMPLE 2 Preparation of(5R)-2-amino-5-(3-bromophenyl)-5-[4-(difluoromethoxy)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one

Using essentially the same procedure described in Example 1, steps a-d,and employing 1-bromo-3-ethynylbenzene in step a, the racemic mixture of2-amino-5-(3-bromophenyl)-5-[4-(difluoromethoxy)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-onewas obtained and separated by chiral chromatography technique (ChiralcelOJ, 2×25 cm, using 5% ethanol in 95% hexane and diethylamine as themobile phase) to give the title enantiomer, MS m/e (M+H)⁺ 332; ¹H NMR(400 MHz, DMSO-d₆)

2.94 (s, 3H), 6.72 (brs, 2H), 7.1 (d, J=8.66 Hz, 2H), 7.13-7.35 (m, 2H),7.38-7.43 (m, 4H), 7.56 (t, J=1.72 Hz, 1H); [a]₂₅=−4 (C=1% in MeOH).

EXAMPLE 3 Preparation of(5R)-2-Amino-5-(3-bromo-4-fluorophenyl)-5-[4-(difluoromethoxy)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one

Using essentially the same procedure described in Example 1, steps a-c,and employing 3-bromo-4-fluoro-1-ethynylbenzene the racemic mixture of2-amino-5-(3-bromo-4-fluorophenyl)-5-[4-(difluoromethoxy)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-onewas obtained and separated by chiral chromatography technique (ChiralcelOJ, 0.46×10 cm, using 15% ethanol in 85% hexane and diethylamine as themobile phase) to give the title enantiomer, MS m/e (M+H)⁺ 332; ¹H NMR(400 MHz, DMSO-d₆)

2.94 (s, 3H), 6.74 (brs, 2H), 7.1 (d, J=8.75 Hz, 2H), 7.13-7.65 (m, 5H),7.67 (d, J=2.2 Hz, 1H); [a]₂₅=−22 (C=1% in MeOH).

EXAMPLE 4 Preparation of(5R)-2-Amino-5-[4-(difluoromethoxy)phenyl]-3-methyl-5-(3-propylphenyl)-3,5-dihydro-4H-imidazol-4-one[A] and(5S)-2-Amino-5-[4-(difluoromethoxy)phenyl]-3-methyl-5-(3-propylphenyl)-3,5-dihydro-4H-imidazol-4-one[B]

Step a) 2-(3-Ethynylphenyl)-1,3-dioxolane

A mixture of ethynyl(trimethyl)silane (36 g, 367 mmol),2-(3-bromophenyl)-1,3-dioxolane (78 g, 342 mmol), N,N-dimethylformamide(400 mL), and triethylamine (1.1 81 mL, mmol) was bubbled with anhydrousargon for 5 minutes, treated with copper iodide (0.94 g, 4.96 mmol) anddichlorobis(triphenylphosphine) palladium(II) (7.7 g, 11.01 mmol),stirred at 60° C. for 3 hours, cooled to room temperature, poured intowater and extracted with ethyl ether. The organic extracts werecombined, dried over MgSO₄ and concentrated in vacuo to give{[3-(1,3-dioxolan-2-yl)phenyl]ethynyl}-(trimethyl)silane as a yellow oil(63 g, 256 mmol). The yellow oil was dissolved in MeOH (600 mL) andCH₂Cl₂ (600 mL), treated with cesium carbonate (91.8 g, 281.6 mmol),stirred at room temperature for 10 h, poured into water and extractedwith ethyl ether. The ether extracts were combined, dried over MgSO₄,concentrated in vacuo and distilled to give2-(3-ethynylphenyl)-1,3-dioxolane as a yellow oil (42 g, 71% yield), MSm/e M⁺ 174; ¹H NMR (400 MHz, DMSO-d₆)

3.9-4.05 (m, 4H), 4.15 (s, 1H), 5.7 (s, 1H), 7.35-7.45 (m, 4H).

Step b) 2-(3-{[4-(Difluoromethoxy)phenyl]ethynyl}phenyl)-1,3-dioxolane

Using essentially the same procedure described in Example 1, step a, andemploying 2-(3-ethynylphenyl)-1,3-dioxolane and1-(difluoromethoxy)-4-iodobenzene, the coupled product was obtained.This product was purified on silica gel (ISCO) using hexanes/EtOAc 5/1as the eluting solvents to give2-(3-{[4-(difluoromethoxy)phenyl]ethynyl}phenyl)-1,3-dioxolane as ayellow oil (7.9 g, 85% yield), MS m/e (M+H)⁺ 317; ¹H NMR (400 MHz,DMSO-d₆)

3.9-4.05 (m, 4H), 5.72 (s, 1H), 7.1-7.3 (m, 3H), 7.4 (m, 2H), 7.5-7.6(m, 4H).

Step c) 3-{[4-(Difluoromethoxy)phenyl]ethynyl}benzaldehyde

Into a mixture of2-(3-{[4-(difluoromethoxy)phenyl]ethynyl}phenyl)-1,3-dioxolane, (1.0 g,3.1 mmol) and THF (5 mL) was added HCl (2N, 1 mL). The mixture wasstirred at room temperature for 2 hours, poured into water and extractedwith EtOAc/ethyl ether 1/1. The organic extracts were dried over MgSO₄.Evaporation and purification on silica gel (ISCO) using hexanes/EtOAc(3/1) as the eluting solvents gave3-{[4-(difluoromethoxy)phenyl]ethynyl}benzaldehyde as a yellow oil (3.65g, 95% yield), MS m/e M⁺ 272; ¹H NMR (400 MHz, DMSO-d₆)

3.9-4.05 (m, 4H), 5.72 (s, 1H), 7.1-7.3 (m, 4H), 7.62 (m, 2H), 7.8-7.9(m, 2H), 8.03 (s, 1H), 9.99 (s, 1H).

Step d)N′-[(1E)-(3-{[4-(Difluoromethoxy)phenyl]ethynyl}phenyl)methylene]-4-methylbenzenesulfonohydrazide

A mixture of 3-{[4-(difluoromethoxy)phenyl]ethynyl}benzaldehyde (3.69 g,13.57 mmol), 4-methylbenzenesulfonohydrazide (2.9 g, 15.6 mmol) and EtOH(11 mL) was refluxed for 30 minutes. cooled to room temperature, pouredinto water and extracted with ethyl ether. The organic extracts werecombined dried over MgSO₄ and concentrated in vacuo. The resultantresidue was purified on silica gel (Biotage) using hexanes/EtOAc (2/1)as the eluting solvents to giveN′-[(1E)-(3-{[4-(difluoromethoxy)phenyl]ethynyl}phenyl)methylene]-4-methylbenzenesulfonohydrazideas a tan solid (5.4 g, 90% yield), MS m/e (M+H)⁺ 441; ¹H NMR (400 MHz,DMSO-d₆)

2.32 (s, 3H), 7.2 (d, J=8.66 Hz, 2H), 7.3-7.6 (m, 8H), 7.72 (d, J=8.3Hz, 2H), 7.88 (s, 1H), 11.54 (s, 1H).

Step e) 1-{[4-(Difluoromethoxy)phenyl]ethynyl}-3-propylbenzene

A mixture ofN′-[(1E)-(3-{[4-(difluoromethoxy)phenyl]ethynyl}phenyl)methylene]-4-methylbenzenesulfonohydrazide(0.67 mg, 1.52 mmol) in THF was treated with triethyl borane (1.0 M inTHF, 1.52 mL, 1.52 mmol), stirred for 2 minutes, treated with NaOH (2.5N, 0.61 mL, 1.52 mmol), refluxed for 2 hours, cooled to roomtemperature, poured into water and extracted with EtOAc. The organicextracts were combined, dried over MgSO₄ and concentrated in vacuo. Theresultant residue was purified on silica gel (ISCO) using hexanes/EtOAc(50/1) as the eluting solvents to give1-{[4-(difluoromethoxy)phenyl]ethynyl}-3-propylbenzene as a clear oil(386 mg, 89% yield), MS m/e (M+H)⁺ 286; ¹H NMR (400 MHz, DMSO-d₆)

0.85 (t, J=7.32 Hz, 3H), 1.57 (m, 2H), 2.6 (t, J=7.32 Hz, 2H), 7.2 (m,3H), 7.35-7.45 (m, 4H), 7.58 (d, J=8.79 Hz, 2H).

Step f) 1-[4-(Difluoromethoxy)phenyl]-2-(3-propylphenyl)ethane-1,2-dione

Using essentially the same procedure described in Example 1, step b, andemploying 1-{[4-(difluoromethoxy)phenyl]ethynyl}-3-propylbenzene, thedione product was obtained. This product was purified on silica gel(ISCO) using hexanes/EtOAc 30/1 as the eluting solvents to give1-[4-(difluoromethoxy)phenyl]-2-(3-propylphenyl)-ethane-1,2-dione ayellow oil (82% yield), MS m/e (M−H)⁺ 317; ¹H NMR (400 MHz, DMSO-d₆)

0.85 (t, J=7.32 Hz, 3H), 1.57 (m, 2H), 2.6 (t, J=7.32 Hz, 2H), 7.35 (d,J=8.78 Hz, 2H), 7.4-7.5 (m, 3H), 7.65-7.7 (m, 2H), 7.95(d, J=8.78 Hz,2H).

Step g)2-Amino-5-[4-(difluoromethoxy)phenyl]-3-methyl-5-(3-propylphenyl)-3,5-dihydro-4H-imidazol-4-one

Using essentially the same procedure described in Example 1, step c andemploying1-[4-(difluoromethoxy)phenyl]-2-(3-propylphenyl)ethane-1,2-dione, thehydantoin product was obtained. This product was purified on silica gel(ISCO) using hexanes/MeOH 20/1 as the eluting solvents to give2-amino-5-[4-(difluoromethoxy)-phenyl]-3-methyl-5-(3-propylphenyl)-3,5-dihydro-4H-imidazol-4-oneas a white solid (91% yield), MS m/e (M+H)⁺ 374; ¹H NMR (400 MHz,DMSO-d₆)

0.85 (t, J=7.2 Hz, 3H), 1.44 (m, 2H), 2.45 (m, 2H), 2.93 (s, 3H), 6.6(brs, 2H), 7.0 (d, J=7.2 Hz, 1H), 7.06 (d, J=8.4 Hz, 2H), 7.1-7.3 (m,4H), 7.4 (d, J=8.54 Hz, 2H).

Step h)(5R)-2-Amino-5-[4-(difluoromethoxy)phenyl]-3-methyl-5-(3-propylphenyl)-3,5-dihydro-4H-imidazol-4-one[A] and(5S)-2-Amino-5-[4-(difluoromethoxy)phenyl]-3-methyl-5-(3-propylphenyl)-3,5-dihydro-4H-imidazol-4-one[B]

The racemic mixture of2-amino-5-[4-(difluoromethoxy)phenyl]-3-methyl-5-(3-propylphenyl)-3,5-dihydro-4H-imidazol-4-onewas separated by chiral chromatography technique (Chiralcel OJ, 0.46×10cm, using 20% ethanol in CO2 (100 bar) and diethylamine as the mobilephase) to produce the two enantiomers:

[A](5R)-2-amino-5-[4-(difluoromethoxy)phenyl]-3-methyl-5-(3-propylphenyl)-3,5-dihydro-4H-imidazol-4-one,MS m/e (M+H)⁺ 374; ¹H NMR (400 MHz, DMSO-d₆) δ 0.85 (t, J=7.2 Hz, 3H),1.44 (m 2H), 2.45 (m, 2H), 2.93 (s, 3H), 6.6 (brs, 2H), 7.0 (d, J=7.2Hz, 1H), 7.06 (d, J=8.4 Hz, 2H), 7.1-7.3 (m, 4H), 7.4 (d, J=8.54 Hz,2H); [a]₂₅=+28 (C=1% in MeOH); and

[B](5S)-2-amino-5-[4-(difluoromethoxy)phenyl]-3-methyl-5-(3-propylphenyl)-3,5-dihydro-4H-imidazol-4-oneMS m/e (M+H)⁺ 374; ¹H NMR (400 MHz, DMSO-d₆)

0.85 (t, J=7.2 Hz, 3H), 1.44 (m 2H), 2.45 (m, 2H), 2.93 (s, 3H), 6.6(brs, 2H), 7.0 (d, J=7.2 Hz, 1H), 7.06 (d, J=8.4 Hz, 2H), 7.1-7.3 (m,4H), 7.4 (d, J=8.54 Hz, 2H); [a]₂₅=−26.6 (C=1% in MeOH).

EXAMPLE 5 Preparation of(5R)-2-amino-5-(3-butylphenyl)-5-[4-(difluoromethoxy)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one[A] and(5S)-2-amino-5-(3-butylphenyl)-5-[4-(difluoromethoxy)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one[B]

Step a) 3-Bromo-N-methoxy-N-methylbenzamide

A mixture of N-methoxymethanamine hydrochloride (22.1 g, 228.5 mmol),diisopropyl ethyl amine (63.5 mL, 365.6 mmol) and CH₂Cl₂ was treateddropwise with 3-bromobenzoyl chloride (15 g, 68.5 mmol) in CH₂Cl₂,stirred at room temperature for 30 minutes, and concentrated undervacuum. The resultant residue was dispersed in water and extracted withethyl ether. The organic extracts were combined, dried over MgSO₄ andconcentrated in vacuo. The resultant residue was purified on silica gel(Biotage) using hexanes/EtOAc (2/1) as the eluting solvents to give3-bromo-N-methoxy-N-methylbenzamide as a tan solid (15.1 g, 90% yield).

Step b) 1-(3-Bromophenyl)butan-1-one

A cold (0° C.) solution of 3-bromo-N-methoxy-N-methylbenzamide (3 g,12.3 mmol) in THF was treated with propylmagnesium bromide (6.15 mL,12.3 mmol), stirred at room temperature for 1 hour, quenched withaqueous NH₄Cl, acidified with HCl (2N) and extracted with ethyl ether.The organic extracts were combined, dried over MgSO₄ and concentratedunder vacuum. Purification of the resultant residue on silica gel(Biotage) using hexanes/EtOAc (20/1) as the eluting solvents gave1-(3-bromophenyl)butan-1-one as a tan solid (2.1 g, 75% yield).

Step c) 1-Bromo-3-butylbenzene

A mixture of 1-(3-bromophenyl)butan-1-one (1.0 g, 4.4 mmol) and diglyme(10 mL) was treated with hydrazine (1.49 g, 44 mmol), stirred at 100° C.for 2 h, treated with KOH (1.23 g, 22 mmol), stirred at 150° C. for 6hours, cooled to room temperature, poured into water and extracted withethyl ether. The organic extracts were combined, dried over MgSO₄ andconcentrated under vacuum. Purification of the resultant residue onsilica gel (ISCO) using hexanes as the eluting solvent gave1-bromo-3-butylbenzene as a clear oil (0.81 g, 86% yield).

Step d) 1-Butyl-3-{[4-(difluoromethoxy)phenyl]ethynyl}benzene

Using essentially the same procedure described in Example 1, step a, andemploying 1-bromo-3-butylbenzene and1-(difluoromethoxy)-4-ethynylbenzene, the phenylethynylbenzene productwas obtained. This product was purified on silica gel (Biotage) usinghexanes/EtOAc 50/1 as the eluting solvents to give1-butyl-3-{[4-(difluoromethoxy)phenyl]ethynyl}benzene as a colorless oil(0.56 g, 28% yield), MS m/e M⁺ 300; ¹H NMR (400 MHz, DMSO-d₆)

0.82 (t, J=7.19 Hz, 3H), 1.25 (m, 2H), 1.55 (m, 2H), 2.56 (t, J=7.56 Hz,2H), 7.2 (m, 3H), 7.35-7.45 (m, 4H), 7.58 (d, J=8.79 Hz, 2H).

Step e) 1-(3-Butylphenyl)-2-[4-(difluoromethoxy)phenyl]ethane-1,2-dione

Using essentially the same procedure described in Example 1, step b, andemploying 1-butyl-3-{[4-(difluoromethoxy)phenyl]ethynyl}benzene, Thedione product was obtained. This product was purified on silica gel(ISCO) using hexanes/EtOAc 30/1 as the eluting solvents to yield1-(3-butylphenyl)-2-[4-(difluoromethoxy)phenyl]-ethane-1,2-dione as ayellow oil (0.39 g, 92% yield), MS m/e (M+H)⁺ 331; ¹H NMR (400 MHz,DMSO-d₆)

0.84 (t, J=7.32 Hz, 3H), 1.26 (m, 2H), 1.51 (m, 2H), 2.63 (t, J=7.56 Hz,2H), 7.35 (d, J=8.78 Hz, 2H), 7.4-7.5 (m, 3H), 7.65-7.7 (m, 2H), 7.95(d, J=8.78 Hz, 2H).

Step f)2-Amino-5-(3-butylphenyl)-5-[4-(difluoromethoxy)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one

Using essentially the same procedure described in Example 1, step c, andemploying1-(3-butylphenyl)-2-[4-(difluoromethoxy)phenyl]ethane-1,2-dione, thehydantoin product was obtained. This product was purified on silica gel(ISCO) using EtOAc/MeOH 20/1 as the eluting solvents to yield2-amino-5-(3-butylphenyl)-5-[4-(difluoromethoxy)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-oneas a white solid, MS m/e (M+H)⁺ 388; ¹H NMR (400 MHz, DMSO-d₆)

0.82 (t, J=7.32 Hz, 3H), 1.25 (m 2H), 1.45 (m, 2H), 2.48 (m, 2H), 2.93(s, 3H), 6.6 (brs, 2H), 7.0 (d, J=7.44 Hz, 1H), 7.1 (d, J=8.78 Hz, 2H),7.12-7.32 (m, 4H), 7.4 (d, J=8.78 Hz, 2H).

Step g)(5R)-2-Amino-5-(3-butylphenyl)-5-[4-(difluoromethoxy)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one[A] and(5S)-2-Amino-5-(3-butylphenyl)-5-[4-(difluoromethoxy)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one[B]

A racemic mixture of2-amino-5-(3-butylphenyl)-5-[4-(difluoromethoxy)-phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-onewas separated by chiral chromatography technique [Chiralcel OJ, 0.46×10cm, using 20% ethanol in CO₂ (100 bar) and diethylamine as the mobilephase] to produce the two enantiomers:

[A](5R)-2-amino-5-(3-butylphenyl)-5-[4-(difluoromethoxy)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one;MS m/e (M+H)⁺ 388; ¹H NMR (400 MHz, DMSO-d₆) δ 0.82 (t, J=7.32 Hz, 3H),1.25 (m 2H), 1.45 (m, 2H), 2.48 (m, 2H), 2.93 (s, 3H), 6.6 (brs, 2H),7.0 (d, J=7.44 Hz, 1H), 7.1 (d, J=8.78 Hz, 2H), 7.12-7.32 (m, 4H), 7.4(d, J=8.78 Hz, 2H); [a]₂₅=+25 (C=1% in MeOH); and

[B](5S)-2-amino-5-(3-butylphenyl)-5-[4-(difluoromethoxy)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one;MS m/e (M+H)⁺ 388, ¹H NMR (400 MHz, DMSO-d₆) δ_(.) 0.82 (t, J=7.32 Hz,3H), 1.25 (m 2H), 1.45 (m, 2H), 2.48 (m, 2H), 2.93 (s, 3H), 6.6 (brs,2H), 7.0 (d, J=7.44 Hz, 1H), 7.1 (d, J=8.78 Hz, 2H), 7.12-7.32 (m, 4H),7.4 (d, J=8.78 Hz, 2H); [a]₂₅=−28.8 (C=1% in MeOH).

EXAMPLES 6-10 Preparation of2-Amino-5-[4-(difluoromethoxy)phenyl]-3-methyl-5-(3-substituted-phenyl)-3,5-dihydro-4H-imidazol-4-oneCompounds

Using essentially the same procedure described in Example 5, steps d-f,and employing the appropriate 1-bromo-3-alkylbenzene and1-(difluoromethoxy-4-ethynylbenzene, the compounds shown below wereobtained and identified by HNMR and mass spectral analyses.

EXAMPLE 62-Amino-5-[4-(difluoromethoxy)phenyl]-3-methyl-5-(3-pentylphenyl)-3,5-dihydro-4H-imidazol-4-one

MS m/e (M+H)⁺ 402; ¹H NMR (400 MHz, DMSO-d₆)

0.72 (t, J=6.83 Hz, 3H), 1.22 (m 4H), 1.44(m, 2H), 2.48 (m, 2H), 2.93(s, 3H), 6.6 (brs, 2H), 7.0 (d, J=7.08 Hz, 1H), 7.1 (d, J=8.66 Hz, 2H),7.12-7.32 (m, 4H), 7.4 (d, J=8.66 Hz, 2H).

EXAMPLE 72-Amino-5-[4-(difluoromethoxy)phenyl]-3-methyl-5-[3-(2-methylbutyl)phenyl]-3,5-dihydro-4H-imidazol-4-one

MS m/e (M+H)⁺ 402; ¹H NMR (400 MHz, DMSO-d₆)

0.7 (d, J=6.58 Hz, 3H), 0.78 (t, J=7.45 Hz, 3H), 1.05 (m, 1H), 1.24 (m,1H), 1.48(m, 1H), 2.23 (m, 1H), 2.51 (m, 2H), 2.93 (s, 3H), 6.61 (brs,2H), 7.0 (d, J=7.07 Hz, 1H), 7.1 (d, J=8.54 Hz, 2H), 7.12-7.32 (m, 4H),7.4 (d, J=8.54 Hz, 2H).

EXAMPLE 82-Amino-5-(3-but-3-en-1-ylphenyl)-5-[4-(difluoromethoxy)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one

MS m/e (M+H)⁺ 386; ¹H NMR (400 MHz, DMSO-d₆)

2.2 (m, 2H), 2.58 (m, 2H), 2.93 (s, 3H), 4.9 (m, 2H), 5.8 (m, 1H), 6.6(brs, 2H), 7.8 (m, 3H), 7.1-7.25 (m, 4H), 7.4 (d, J=8.79 Hz, 2H).

EXAMPLE 92-Amino-5-[3-(cyclopropylmethyl)phenyl]-5-[4-(difluoromethoxy)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one

MS m/e (M+H)⁺ 386; ¹H NMR (400 MHz, DMSO-d₆)

0.08 (m, 2H), 0.38 (m, 2H), 0.87 (m, 1H), 2.41 (d, J=6.96 Hz, 1H), 2.93(s, 3H), 6.6 (brs, 2H), 7.04 (d, J=8.67 Hz, 2H), 7.1-7.3 (m, 5H), 7.44(d, J=8.67 Hz, 2H).

EXAMPLE 103-(3-{2-Amino-4-[4-(difluoromethoxy)phenyl]-1-methyl-5-oxo-4,5-dihydro-1H-imidazol-4-yl}phenyl)propanenitrile

MS m/e (M−H)⁺ 383; ¹H NMR (400 MHz, DMSO-d₆)

2.7 (m, 2H), 2.8 (m, 2H), 2.93 (s, 3H), 6.62 (brs, 2H), 7.05 (d, J=8.66Hz, 2H), 7.15 (m, 2H), 7.21 (t, J=7.45 Hz, 1 H), 7.3 (m, 2H), 7.43 (d,J=8.66 Hz, 2H).

EXAMPLE 11 Preparation of(5R)-2-Amino-5-[4-(difluoromethoxy)phenyl]-3-methyl-5-(3-pent-4-en-1-ylphenyl)-3,5-dihydro-4H-imidazol-4-one[A] and(5S)-2-Amino-5-[4-(difluoromethoxy)phenyl]-3-methyl-5-(3-pent-4-en-1-ylphenyl)-3,5-dihydro-4H-imidazol-4-one[B]

Step a) 1-(3-Bromophenyl)pent-4-en-1-one

A mixture of magnesium (0.48 g, 20.29 mmol) in THF was treated dropwisewith (bromomethyl)cyclopropane (2.49 g, 18.45 mmol) in THF, heated atreflux temperature for 1 hour, poured into a cold (0° C.) mixture of3-bromo-N-methoxy-N-methylbenzamide (2.5 g, 10.24 mmol) and THF, allowedto come to room temperature, stirred for 10 min, quenched with aqueousNH₄Cl and extracted with ethyl ether. The organic extracts werecombined, dried over MgSO₄ and concentrated in vacuo. Purification ofthe resultant residue on silica gel (ISCO) using hexanes/EtOAc 10/1 asthe eluting solvents gave a clear oil (2.4 g, 54% yield), MS m/e (M−H)⁺239; ¹H NMR (400 MHz, DMSO-d₆)

2.3 (m, 2H), 3.1 (t, J=7.19 Hz, 2H), 5.02 (m, 2H), 5.8 (m, 1H), 7.47 (t,J=7.93 Hz, 2H), 7.77 (dd, J=7.08, 2.2 Hz), 7.94 (dd, J=7.81, 1.58 Hz),8.04 (t, J=1.83 Hz, 1H).

Step b)2-Amino-5-[4-(difluoromethoxy)phenyl]-3-methyl-5-(3-pent-4-en-1-ylphenyl)-3,5-dihydro-4H-imidazol-4-one

Using essentially the same procedure described in Example 5, steps d-f,and employing 1-(3-bromophenyl)pent-4-en-1-one and1-(difluoromethoxy)-4-ethynylbenzene,2-amino-5-[4-(difluoromethoxy)phenyl]-3-methyl-5-(3-pent-4-en-1-ylphenyl)-3,5-dihydro-4H-imidazol-4-oneis obtained, MS m/e (M+H)⁺ 400, ¹H NMR (400 MHz, DMSO-d₆)

21.6 (m, 2H), 1.9 (m, 2H), 2.5 (m, 1H), 2.93 (s, 3H), 4.9 (m, 2H), 5.78(m, 1H), 6.6 (brs, 2H), 7-7.08 (m, 3H), 7.1-7.3 (m, 4H), 7.4 (d, J=8.67Hz, 2H)

Step c)(5R)-2-Amino-5-[4-(difluoromethoxy)phenyl]-3-methyl-5-(3-pent-4-en-1-ylphenyl)-3,5-dihydro-4H-imidazol-4-one[A]and(5S)-2-Amino-5-[4-(difluoromethoxy)phenyl]-3-methyl-5-(3-pent-4-en-1-ylphenyl)-3,5-dihydro-4H-imidazol-4-one[B]

A racemic mixture of2-amino-5-[4-(difluoromethoxy)phenyl]-3-methyl-5-phenyl-3,5-dihydro-4H-imidazol-4-onewas separated by chiral chromatography technique (Chiralpak AD, 0.46×25cm, using 10% ethanol in 90% hexane and diethylamine as the mobilephase) to produce the two enantiomers:

[A](5R)-2-amino-5-[4-(difluoromethoxy)phenyl]-3-methyl-5-(3-pent-4-en-1-ylphenyl)-3,5-dihydro-4H-imidazol-4-one,MS m/e (M+H)⁺ 400, ¹H NMR (400 MHz, DMSO-d₆) δ_(.) 21.6 (m, 2H), 1.9 (m,2H), 2.5 (m, 1H), 2.93 (s, 3H), 4.9 (m, 2H), 5.78 (m, 1H), 6.6 (brs,2H), 7-7.08 (m, 3H), 7.1-7.3 (m, 4H), 7.4 (d, J=8.67 Hz, 2H); [a]₂₅=+23(C=1% in MeOH); and

[B](5S)-2-amino-5-[4-(difluoromethoxy)phenyl]-3-methyl-5-(3-pent-4-en-1-ylphenyl)-3,5-dihydro-4H-imidazol-4-one,MS m/e (M+H)⁺ 400, ¹H NMR (400 MHz, DMSO-d₆) δ_(.) 21.6 (m, 2H), 1.9 (m,2H), 2.5 (m, 1H), 2.93 (s, 3H), 4.9 (m, 2H), 5.78 (m, 1H), 6.6 (brs,2H), 7-7.08 (m, 3H), 7.1-7.3 (m, 4H), 7.4 (d, J=8.67 Hz, 2H); [a]₂₅=−19(C=1% in MeOH).

EXAMPLE 12 Preparation ofN-(3-{(4R)-2-Amino-4-[4-(difluoromethoxy)phenyl]-1-methyl-5-oxo-4,5-dihydro-1H-imidazol-4-yl}phenyl)-2-methoxyacetamide[A] andN-(3-{(4S)-2-Amino-4-[4-(difluoromethoxy)phenyl]-1-methyl-5-oxo-4,5-dihydro-1H-imidazol-4-yl}phenyl)-2-methoxyacetamide[B]

Step a) 3-{[4-(difluoromethoxy)phenyl]ethynyl}aniline

Using essentially the same procedure described in Example 1, step a, andemploying 3-ethynylaniline and 1-(difluoromethoxy)-4-iodobenzene, thephenylethynylaniline product was obtained. This product was purified onsilica gel (ISCO) using EtOAc/hexanes 1/3 as the eluting solvents togive 3-{[4-(difluoromethoxy)phenyl]ethynyl}aniline as a yellow solid(95% yield), MS m/e (M+H)⁺ 260; ¹H NMR (400 MHz, DMSO-d₆)

5.26 (brs, 2H), 6.6 dd(, J=8.17, 2.31 Hz, 1H), 6.67 (dd, 7.44, 2.43 Hz,1H), 6.72 (d, J=2.4 Hz, 1H), 7.05 (t, J=7.81 Hz, 1H), 7.43 (d, J=6.1 Hz,2H), 8.55 (d, J=6.1 Hz, 2H).

Step b)N-(3-{[4-(Difluoromethoxy)phenyl]ethynyl}phenyl)-2-methoxyacetamide

A cold (0° C.) solution of 3-{[4-(difluoromethoxy)phenyl]ethynyl}aniline(1 g, 3.86 mmol), triethylamine (0.65 mL, 4.63 mmol) in CH₂Cl₂ wastreated dropwise with methoxyacetyl chloride (0.5 g, 4.63 mmol), allowedto come to room temperature, stirred for 2 hours, poured into water andextracted with EtOAc/ethyl ether 1/1. The organic extracts werecombined, dried over MgSO₄ and concentrated in vacuo. Purification ofthe resultant residue on silica gel (Biotage) using hexanes/EtOAc (1/1)as the eluting solvent gaveN-(3-{[4-(difluoromethoxy)phenyl]ethynyl}phenyl)-2-methoxyacetamide as ayellow solid (1.25 g, 94% yield), MS m/e (M+H)⁺ 332; ¹H NMR (400 MHz,DMSO-d₆)

3.30 (s, 3H), 3.97 (s, 2H), 7.2 (m, 3H), 7.3 (m, 2H), 7.6 (m, 3H),7.9(t, J=1.7 Hz, 1H), 9.84 (s, 1H).

Step c)N-{3-[[4-(Difluoromethoxy)phenyl](oxo)acetyl]phenyl}-2-methoxyacetamide

A mixture ofN-(3-{[4-(difluoromethoxy)phenyl]ethynyl}phenyl)-2-methoxyacetamide(0.68 g, 2.05 mmol), acetone, H₂O, NaHCO₃ (0.1 g, 1.23 mmol), and MgSO₄(0.37 g, 3.07 mmol) was treated with KMnO4 (0.32 g, 2.05 mmol), stirredat room temperature for 4 h and filtered. The filtrate was diluted withwater and extracted with ethyl ether. The organic extracts werecombined, dried over MgSO₄ and concentrated in vacuo. Purification ofthe resultant residue on silica gel (Biotage) using hexanes/EtOAc (1/1)as the eluting solvent gaveN-{3-[[4-(difluoromethoxy)phenyl](oxo)acetyl]phenyl}-2-methoxyacetamideas a yellow oil (0.73 g, 98% yield), MS m/e (M+H)⁺ 364; ¹H NMR (400 MHz,DMSO-d₆)

3.32 (s, 3H), 3.96 (s, 2H), 7.34 (d, J=8.91 Hz, 2H), 7.5-7.6 (m, 3H),7.97 (d, J=8.91 Hz, 2H), 8.05 (dd, J=7.81, 1.7 Hz, 1H), 8.27 (t, J=1.7Hz, 1H), 10.06 (s, 1H).

Step d)N-(3-{2-Amino-4-[4-(difluoromethoxy)phenyl]-1-methyl-5-oxo-4,5-dihydro-1H-imidazol-4-yl}phenyl)-2-methoxyacetamide

Using essentially the same procedure described in Example 1, step c, andemployingN-{3-[[4-(difluoromethoxy)phenyl](oxo)acetyl]phenyl}-2-methoxyacetamide,the hydantoin product is obtained. This product was purified on silicagel (ISCO) using EtOAc/MeOH 10/1 as the eluting solvents to giveN-(3-{2-amino-4-[4-(difluoromethoxy)phenyl]-1-methyl-5-oxo-4,5-dihydro-1H-imidazol-4-yl}phenyl)-2-methoxyacetamideas a white solid (0.15 g, 70% yield), MS m/e (M+H)⁺ 419; ¹H NMR (400MHz, DMSO-d₆)

2.93 (s, 3H), 3.30 (s, 3H), 3.90 (s, 2H), 6.61 (brs, 2H), 7.08 (m, 3H),7.2 (m, 2H), 7.44 (d, J=8.78 Hz, 2H), 7.55 (d, J=7.93 Hz, 1H), 7.62 (s,1H), 9.71 (s, 1H).

Step e)N-(3-{(4R)-2-Amino-4-[4-(difluoromethoxy)phenyl]-1-methyl-5-oxo-4,5-dihydro-1H-imidazol-4-yl}phenyl)-2-methoxyacetamide

A racemic mixture ofN-(3-{2-amino-4-[4-(difluoromethoxy)phenyl]-1-methyl-5-oxo-4,5-dihydro-1H-imidazol-4-yl}phenyl)-2-methoxyacetamidewas separated by chiral chromatography technique (Chiralcel AD, 2×25 cm,using 25% isopropanol in 75% hexane and diethylamine as the mobilephase) to produce the two enantiomers as white solids:

[A]N-(3-{(4R)-2-amino-4-[4-(difluoromethoxy)phenyl]-1-methyl-5-oxo-4,5-dihydro-1H-imidazol-4-yl}phenyl)-2-methoxyacetamide,MS m/e (M+H)⁺ 419; ¹H NMR (400 MHz, DMSO-d₆)

2.93 (s, 3H), 3.30 (s, 3H), 3.90 (s, 2H), 6.61 (brs, 2H), 7.08 (m, 3H),7.2 (m, 2H), 7.44 (d, J=8.78 Hz, 2H), 7.55 (d, J=7.93 Hz, 1H), 7.62 (s,1H), 9.71 (s, 1H); [a]₂₅=+18 (C=1% in MeOH); and

[B]N-(3-{(4S)-2-amino-4-[4-(difluoromethoxy)phenyl]-1-methyl-5-oxo-4,5-dihydro-1H-imidazol-4-yl}phenyl)-2-methoxyacetamide,MS m/e (M+H)⁺ 419; ¹H NMR (400 MHz, DMSO-d₆)

2.93 (s, 3H), 3.30 (s, 3H), 3.90 (s, 2H), 6.61 (brs, 2H), 7.08 (m, 3H),7.2 (m, 2H), 7.44 (d, J=8.78 Hz, 2H), 7.55 (d, J=7.93 Hz, 1H), 7.62 (s,1H), 9.71 (s, 1H); [a]₂₅=−16 (C=1% in MeOH).

EXAMPLE 13 Preparation of2-Amino-5-[4-(difluoromethoxy)phenyl]-3-methyl-5-[3-(4,4,4-trifluorobutyl)phenyl]-3,5-dihydro-4H-imidazol-4-one

Step a) 3-Bromo-N-methoxy-N-methylbenzamide

A solution of 3-bromobenzoyl chloride (20 g, 91.1 mmol) in CH₂Cl₂ wasadded dropwise to a cold (0° C.) solution of N, O-dimethylhydroxylaminehydrochloride (33.6 g, 319 mmol), diisopropylamine (98 mL, 551 mmol) inCH₂Cl₂ over 1 hour. The stirring continued at room temperature for 30minutes then concentrated under vacuo. The resultant residue wasdispersed in water and extracted with ethyl ether. The organic extractswere combined, dried over MgSO₄ and concentrated in vacuo. This residuewas purified on silica gel (ISCO) using hexanes/EtOAc (4/1) as theeluting solvent to give 3-bromo-N-methoxy-N-methylbenzamide as lightyellow solid (20 g, 89% yield). m/e (M+H)⁺ 244. ¹H NMR (400 MHZ,DMSO-d₆) δ ppm, 3.21 (s, 3H), 3.50 (s, 3H), 7.37-7.39, (m, 1H),7.53-7.55 (m, 1H), 7.64-7.66 (m, 1H), 7.67-7.69 (m, 1H).

Step b) 1-(3-Bromo-phenyl)-4,4,4-trifluoro-butan-1-one

A prepared solution of trifluoromethyl ethane-magnesium bromide (made byrefluxing Mg with 1-bromo, 2-trifluoromethyl ethane in THF for 2 hours;4.6 g=25.82 mmol) in THF was added slowly to a cold (0° C.) solution of3-bromo-N-methoxy-N-methylbenzamide (3.5 g, 14.3 mmol) in THF. Thestirring continued at room temperature for 1 hour, quenched with coldsaturated aqueous NH₄Cl, acidified with 1 N HCl and extracted with ethylether. The organic extracts were combined, dried over MgSO₄ andconcentrated in vacuo. The crude product was purified on silica gel(ISCO) using hexanes/EtOAc (10/1) as the eluting solvent to give1-(3-Bromo-phenyl)-4,4,4-trifluoro-butan-1-one as a colorless oil (3.1g, 77% yield). m/e (M−H)⁻ 279, 1H NMR (400 MHz, DMSO-d₆) δ ppm, 2.5-2.6(m, 2 H), 3.3-3.4 (m, 2 H), 7.5 (t, J=7.9 Hz, 1 H), 7.8-7.8 (m, 1 H),7.9-8.0 (m, 1 H), 8.1 (t, J=1.7 Hz, 1 H).

Step c) 1-Bromo-3-(4,4,4-trifluoro-butyl)-benzene

A mixture of 1-(3-bromo-phenyl)-4,4,4-trifluoro-butan-1-one (3.1 g, 11mmol) and diglyme was treated with hydrazine mono hydrate (5.5 g, 110.3mmol), and stirred at 100° C. for 2 hours then treated with powder KOH(3.1 g, 55.1 mmol). The stirring continued at 150° C. for 6 hours. Themixture was cooled to room temperature, poured into a mixture ofice/water and extracted with ethyl ether. The extracts were combined,dried over MgSO₄ and concentrated in vacuo. The crude product waspurified on silica gel (ISCO) using hexanes as the eluting solvent togive 1-Bromo-3-(4,4,4-trifluoro-butyl)-benzene as a colorless oil (2.4g, 88% yield). m/e (M)⁺ 266; ¹H NMR (400 MHZ, DMSO-d₆) δ ppm, 1.7-1.8(m, 2 H), 2.1-2.2 (m, 2 H), 2.6 (t, J=7.6 Hz, 2 H), 7.2-7.25 (m, 2 H),7.3-7.35 (m, 1 H), 7.4 (s, 1 H)

Step d)1-Difluoromethoxy-4-[3-(4,4,4-trifluorobutyl)phenylethynyl]benzene

Using essentially the same procedure described in Example 1, Step a,1-difluoromethoxy-4-[3-(4,4,4-trifluorobutyl)phenylethynyl]benzene wasobtained as a colorless oil (0.19 g, 30% yield). m/e (M)⁺ 354; ¹H NMR(400 MHZ, DMSO-d-₆) δ ppm, 1.74-1.78 (m, 2H), 2.17-2.21 (m, 2H),2.62-266 (t, J=7.65 Hz, 2H), 7.17-7.20 (d, J=8.8 Hz, 2H), 7.23-7.39 (m,5H), 7.56-7.58 (d, J=8.8 Hz, 2H).

Step e)1-(4-Difluoromethoxyphenyl)-2-[3-(4,4,4-trifluorobutyl)phenyl]ethane-1,2-dione

A solution of1-difluoromethoxy-4-[3-(4,4,4-trifluorobutyl)phenylethynyl]-benzene(7.62 mmol) in acetone is treated with MgSO₄ (1.83 g, 15.25 mmol)followed by an aqueous solution of NaHCO₃ (0.38 g, 4.57 mmol) in H₂O andKMnO₄ (2.41 g, 15.24 mmol). The suspension is stirred for 20 hours,diluted with H₂O and ether and filtered through a pad of solka floc. Thefiltrate is extracted with ether. The extracts are washed with brine,dried over MgSO₄ and concentrated in vacuo to give1-(4-difluoromethoxyphenyl)-2-[3-(4,4,4-trifluorobutyl)phenyl]ethane-1,2-dioneas a yellow oil. m/e (M−H)⁻ 385; ¹H NMR (400 MHZ, CDCl₃) δ ppm, 1.8-1.9(m, 2 H), 2.0-2.1 (m, 2 H), 2.7 (t, J=7.8 Hz, 2 H), 6.6 (t, J=72.6 Hz, 1H), 7.2-7.2 (m, 2 H), 7.4-7.5 (m, 2 H), 7.7-7.8 (m, 2 H), 8.0-8.0 (m, 2H),

Step f)2-Amino-5-[4-(difluoromethoxy)phenyl]-3-methyl-5-[3-(4,4,4-trifluorobutyl)phenyl]-3,5-dihydro-4H-imidazol-4-one

Using essentially the same procedure described in Example 1, Step c, thetitle product was obtained as a white solid, 0.11 g (55% yield), mp 70°C.; m/e (M−H)⁻ 440.1; ¹H NMR (400 MHZ, DMSO-d₆) δ ppm, 1.64-1.68 (dd,J=7.9 Hz, 2H), 2.16-219 (m, 2H), 2.54-2.58 (t, J=7.76 Hz, 2H), 2.93 (s,3H), 6.61 (bs, 2H), 6.93+7.3 (s, 1H), 7.04-7.06 (d, J=8.81 Hz, 2H),7.18-7.19 (t, J=7.6 Hz, 1H), 7.23 (m, 3H), 7.40-7.42 (d, J=8.81 Hz, 2H).

EXAMPLE 14 Preparation of5-(3-{2-Amino-4-[4-(difluoromethoxy)phenyl]-1-methyl-5-oxo-4,5-dihydro-1H-imidazol-4-yl}phenyl)pentanenitrile

Step a) 4-(3-Bromophenyl)-4-oxo-butyronitrile

A mixture of powder sodium cyanide (1.23 g, 25 mmol) in DMF was treatedslowly with a solution of 3-bromo-benzaldehyde in DMF, stirred at 35° C.for 3 hours, cooled to room temperature, poured into a cold 0.5 N HClsolution and extracted with ethyl ether. The extracts were combined,washed with saturated aqueous sodium bicarbonate, brine, dried overMgSO₄ and concentrated in vacuo. The resultant residue was triturated inethyl ether and filtered. The filtercake was dried to give4-(3-bromophenyl)-4-oxo-butyronitrile as a yellow solid (4 g, 58%yield). m/e (M)⁺ 237. ¹H NMR (400 MHZ, DMSO-d₆) δ ppm, 2.7 (t, J=6.7 Hz,2 H), 3.5 (t, J=6.7 Hz, 2 H), 7.5 (t, J=7.8 Hz, 1 H), 7.9 (ddd, J=7.9,2.1, 0.9 Hz, 1 H), 8.0 (ddd, J=7.8, 1.7, 0.9 Hz, 1 H), 8.1 (t, J=1.7 Hz,1 H).

Step b) 4-(3-Bromophenyl)butyric acid

The title compound was prepared in substantially the same manner asdescribed in (example 3 step c) and was obtained as light brown oil(2.85 g, 93% yield. m/e (M−H)⁻ 241. ¹H NMR (400 MHZ, DMSO-d₆)

ppm, 1.7-1.8 (m, 2 H), 2.2 (t, J=7.4 Hz, 2 H), 2.6 (t, J=7.9 Hz, 2 H),7.2-7.2 (m, 1 H), 7.3 (t, J=7.5 Hz, 1 H), 7.4-7.4 (m, 1 H), 7.4-7.4, (m,1 H), 12.1 (s, 1 H).

Step c) 4-(3-Bromophenyl)butan-1-ol

A cold (0° C.) solution of 4-(3-bromophenyl)butyric acid (2.85 g, 11.7mmol) in THF was treated slowly with a solution of B₂H₆-THF (35 mL),stirred at room temperature for 18 hours, poured into ice/water,basified with 2.5 N NaOH to pH=11 and extracted with CH₂Cl₂. Theextracts were combined, washed with brine, dried over MgSO₄ andconcentrated in vacuo. Purification of the resultant residue by columnchromatography using hexanes/CH₂Cl₂/MeOH (4/4.5/0.5) as the elutingsolvent afforded 4-(3-bromophenyl)butan-1-ol as a colorless oil (1.9 g,70% yield. m/e (M)⁺ 228; ¹H NMR (400 MHZ, DMSO-d₆) δ ppm, 1.3-1.4 (m, 2H) 1.5-1.6 (m, 2 H), 2.55-2.59 (m, 2 H), 3.3-3.38 (m, 2H), 4.3 (t,J=7.5, 1H), 7.2-7.2 (m, 1 H), 7.3 (t, J=7.5 Hz, 1 H), 7.4-7.4 (m, 1 H),7.4-7.4 (m, 1 H).

Step d) Toluene-4-sulfonic acid 4-(3-bromo-phenyl)butyl ester

A cold (0° C.) solution of 4-(3-bromophenyl)butan-1-ol (1.08 g, 4.7mmol) and p-toluenesulfonyl chloride (1.2 g, 6.3 mmol) in THF wastreated slowly with triethyl amine (1.8 mL, 12.3 mmol), stirred at roomtemperature for 4 hours, poured into cold saturated aqueous NH₄Cl andextracted with ether. The organic extracts were combined, washed withbrine, dried over MgSO₄ and concentrated in vacuo. Purification of theresultant residue on silica gel (ISCO) using (hexanes/EtOAC 9.5/0.5) asthe eluting solvent afforded toluene-4-sulfonic acid4-(3-bromophenyl)-butyl ester as a colorless oil (2.4 g, 76% yield). m/e(M+NH₄)⁺ 400.1. ¹H NMR (400 MHZ, DMSO-d₆) δ ppm, 1.4-1.6 (m, 4 H), 2.4(s, 3 H), 2.4-2.5 (m, 2 H), 4.0 (t, J=6.0 Hz, 2 H), 7.2 (t, J=7.8 Hz, 1H), 7.3-7.3 (m, 1 H), 7.3-7.3 (m, J=8.0, 1.0 Hz, 1 H), 7.4-7.5 (m, J=8.6Hz, 2 H), 7.7-7.8 (m, 2 H).

Step e) 5-(3-Bromophenyl)pentanenitrile

A mixture of toluene-4-sulfonic acid 4-(3-bromophenyl)butyl ester (2.3g, 6 mmol) and powdered sodium cyanide (0.65 g, 13 mmol) in DMSO washeated up to 80° C., stirred for 1.5 hours and monitored by NMR. Whenthe reaction was complete, the reaction mixture was cooled to roomtemperature, diluted with H₂O and extracted with CH₂Cl₂. The combinedorganic extracts were washed with brine, dried over MgSO₄ andconcentrated in vacuo. Purification of this residue on silica gel (ISCO)using (hexanes/EtOAC 9.5/0.5) as the eluting solvent gave5-(3-bromo-phenyl)pentanenitrile as a colorless oil (1.12 g, 78% yield).m/e (M)⁺ 237; ¹H NMR (400 MHZ, DMSO-d₆) δ ppm, 2.63-2.65 (m, 2H),2.75-2.78 (m, 2H), 2.35-2.38 (m, 2H), 2.60-2.63 (m, 2H), 7.05-7.10 (m,2H), 7.25-7.28 (m, 2H).

Step f) 5-[3-(4-Difluoromethoxyphenylethynyl)phenyl]pentanenitrile

Using essentially the same procedure described in Example 1, Step a,5-[3-(4-difluoromethoxyphenylethynyl)phenyl]pentanenitrile was obtainedas a light brown oil (0.54 g, 88% yield). m/e (M+H)⁺ 326. ¹H NMR (400MHZ, DMSO-d₆) δ ppm, 1.5-1.6 (m, 2 H), 1.6-1.7 (m, 2 H), 2.5 (t, J=7.0Hz, 2 H), 2.6 (t, J=7.5 Hz, 2 H), 7.3 (dd, J=73.7 Hz, 1 H), 7.2-7.3 (m,2 H), 7.3 (t, J=7.4 Hz, 1 H), 7.4-7.4 (m, 1 H), 7.4-7.4 (m, 1 H).

Step g)5-{3-[2-(4-Difluoromethoxyphenyl)-2-oxo-acetyl]phenyl}pentanenitrile

Using essentially the same procedure described in Example 13, Step e,5-{3-[2-(4-difluoromethoxyphenyl)-2-oxo-acetyl]phenyl}pentanenitrile wasobtained as a light yellow oil (0.46 g, 77% yield). m/e (M+H)⁺ 358; ¹HNMR (400 MHZ, CDCl₃) δ 1.20 ppm, 1.6-1.8 (m, 2 H), 1.7-2.0 (m, 2 H),2.3-2.5 (m, J=7.0, 7.0 Hz, 2 H), 2.6-2.9 (m, J=7.5, 7.5 Hz, 2 H), 6.6(t, J=72.7 Hz, 1 H), 7.2-7.4 (m, 2 H) 7.4-7.6, (m, 2 H) 7.6-7.9, (m, 2H), 7.9-8.2 (m, 2 H).

Step h)5-(3-{2-Amino-4-[4-(difluoromethoxy)phenyl]-1-methyl-5-oxo-4,5-dihydro-1H-imidazol-4-yl}phenyl)pentanenitrile

Using essentially the same procedure described in Example 1, Step c, thetitle product was obtained as a white solid, 0.23 g (43% yield), mp 65°C.; m/e (M+H)⁺ 413 ¹H NMR (400 MHZ, DMSO-d₆) δ ppm, 1.4-1.6 (m, 4 H),2.4-2.5 (m, 2 H), 2.5 (t, J=7.2 Hz, 2 H), 2.9 (s, 3 H), 6.6 (bs., 2 H),7.1 (t, J=74.2 Hz, 1 H), 7.0-7.1 (m, 3 H), 7.2 (t, J=7.8 Hz, 1 H),7.2-7.2, (m, 2 H), 7.4-7.5 (m, 2 H).

EXAMPLE 15 Preparation of4-(3-{2-amino-4-[4-(difluoromethoxy)phenyl]-1-methyl-5-oxo-4,5-dihydro-1H-imidazol-4-yl}phenyl)butanenitrile

Using essentially the same procedure described in Example 14 andemploying 3-(3-bromophenyl)propanoic acid, the title product wasobtained as a white solid, 0.23 g (48% yield), mp 75° C.; m/e (M+H)⁺399. ¹H NMR (400 MHZ, DMSO-d₆) δ ppm, 1.73-1.76 (m, 2 H), 2.44-2.46 (m,2 H), 2.55-2.59 (t, J=7.8 Hz, 2 H), 2.9 (s, 3 H), 6.6 (bs., 2 H),7.05-7.07 (d, J=8.7 Hz, 2 H), 7.13-7.32 (m, 5 H), 7.41-7.43 (d, J=8.7Hz, 2 H).

EXAMPLE 16 Preparation of2-Amino-5-[3-(1,4-difluorobutyl)phenyl]-5-[4-(difluoromethoxy)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one

Step a) 4-(3-Bromophenyl)but-3-yn-1-ol

A solution of 10.0 gm (35.3 mmol) of 3-iodo-bromobenzene in DMF wastreated with 2.95 mL (88 mmol) of 4-butyne-1-ol, 0.2 gm (1.06 mmol) ofcopper (I) iodide, 1.23 gm ofdichlorobis(triphenylphosphine)-palladium(II), and 49 mL (0.35 mol) oftriethylamine, stirred at room temperature for 18 h, poured into waterand extracted with EtOAc. The combined extracts were washed sequentiallywith water and brine, dried over Na₂SO₄ and concentrated at reducedpressure. Chromatography of the resultant concentrate on silica gel witha gradient of 5% to 30% EtOAc-hexanes afforded4-(3-bromophenyl)but-3-yn-1-ol as an orange oil, 7.3 gm (92% yield); ¹HNMR (400 MHz, CDCl₃) δ: 1.79 (s, 1H), 2.67 (t, 2H, J=6.3 Hz), 3.80 (t,2H, J=6.3 Hz), 7.14 (t, 1H, J=7.9 Hz), 7.30 (d, 1H, J=7.9 Hz), 7.41 (m,1H), 7.54 (t, 1H, J=1.6 Hz).

Step b) 1-Bromo-3-(4-fluoro-but-1-ynyl)benzene

A solution of 1.5 gm (6.67 mmol) of 4-(3-bromophenyl)but-3-yn-1-ol inCH₂Cl₂ at 0° C. was treated with 2.0 mL (15.3 mmol) of DAST, stirred at0° C. for 1 h, allowed to warm to room temperature for 1 h, poured intosaturated sodium bicarbonate and extracted with EtOAc. The combinedextracts were washed sequentially with water and brine, dried overNa₂SO₄ and concentrated under reduced pressure. Chromatography of theresultant concentrate on silica gel with a gradient of 0% to 24%EtOAc-hexanes gave 1-Bromo-3-(4-fluoro-but-1-ynyl)benzene as a volatileliquid, 0.96 gm (64% yield); ¹H NMR (400 MHz, CDCl₃) δ: 2.82 (dt, 2H,J=6.6, 19.8 Hz), 4.56 (dt, 2H, J=6.6,46.4 Hz), 7.14 (t, 2H, J=7.9 Hz),7.31 (m, 1H), 7.41 (m, 1H), 7.55 (t, 1H, J=1.7 Hz).

Step c) 1-(3-Bromophenyl)-4-fluorobutan-1-one

A mixture of 0.2 gm (0.89 mmol) of1-bromo-3-(4-fluorobut-1-ynyl)benzene, 2 mL of MeOH, 1 mg ofmethyl(triphenylphosphine)gold (I), 25 μL of conc. H₂SO₄ and 0.44 mL ofH₂O was placed in a sealed tube, flushed with argon, heated to 72° C.for 2 h and was cooled. The reaction mixture was diluted with EtOAc,washed sequentially with water and brine, dried over Na₂SO₄ andconcentrated under reduced pressure. Chromatography of the concentrateon silica gel with a gradient of 0% to 20% EtOAc-hexanes gave1-(3-bromophenyl)-4-fluorobutan-1-one as an oil, 0.086 gm (40% yield);¹H NMR (400 MHz, CDCl₃) δ: 2.13 (m, 2H), 3.09 (t, 2H, J=7.1 Hz), 4.53(dt, 2H, J=5.8, 47.1 Hz), 7.33 (t, 1H, J=7.8 Hz), 7.66 (dq, 1H, J=1.0,7.8 Hz), 7.55 (dq, 1H, J=1.0, 7.8 Hz), 8.07 (t, 1H, J=1.7 Hz).

Step d) 1-Bromo-3-(1,4-difluoro-butyl)benzene

A solution of 0.3 gm (1.22 mmol) of1-(3-bromo-phenyl)-4-fluorobutan-1-one in THF at 0° C. was treated with0.055 gm (1.47 mmol) of solid NaBH₄, stirred at 0° C. for 0.5 h, allowedto warm to room temperature, stirred for 18 h, quenched with aqueousNH₄Cl and poured into EtOAC. The phases were separated. The organicphase was washed sequentially with water and brine, dried over Na₂SO₄and concentrated under reduced pressure to give1-(3-bromophenyl)-4-fluorobutan-1-ol as an oil, 0.29 gm (96% yield) ofan oil. This oil was dissolved in CH₂Cl₂, cooled to 0° C., treated with0.23 mL (1.75 mmol) of DAST, stirred at 0° C. for 0.5 h, allowed to warmto room temperature, and stirred at room temperature for 18 h, quenchedwith water and poured into EtOAc. The phases were separated. The organicphase was washed sequentially with water and brine, dried over Na₂SO₄and carefully concentrated at reduced pressure. The concentrate was usedwithout further purification in Step e.

Step e)1-(3-{[4-(Difluoromethoxy)phenyl]ethynyl}phenyl)-1,4-difluorobutane

To a degassed solution of 13 mg (0.034 mmol) ofbis(benzonitrile)dichloropalladium (II) in dioxane was added 0.145 gm(0.072 mmol) of a 10% (wt/wt) tri-t-butylphosphine in hexanes. Thereaction mixture was stirred for 15 minutes at room temperature, treatedwith 4.3 mg of copper(I) iodide followed by 0.21 mL of diisopropylamine,stirred for 10 min, treated with 0.28 gm (1.14 mmol) of1-bromo-3-(1,4-difluoro-butyl)benzene and 0.25 gm (1.48 mmol) of1-difluoromethoxy-4-ethynylbenzene dissolved in 2 mL of dioxane. Thereaction mixture was heated to 35° C. for 0.5 h, allowed to cool to roomtemperature, stirred at room temperature for 3 h, poured into EtOAc. Theorganic phase was separated, washed sequentially with water and brine,dried over Na₂SO₄ and concentrated under reduced pressure.Chromatography of the concentrate on silica gel with a gradient of 0% to25% EtOAc-hexanes afforded1-(3-{[4-(difluoromethoxy)phenyl]ethynyl}phenyl)-1,4-difluorobutane asan oil, 0.314 gm (82% yield); ¹H NMR (400 MHz, CDCl₃) δ: 1.77-2.07 (m,4H), 4.51 (m, 2H), 5.48 (dq, 1H, J=4.4, 47.6 Hz), 6.51 (t, 1H, J=73.5Hz), 7.08 (d, 1H, J=8.6 Hz), 7.22-7.36 (m, 3H), 7.45-7.52 (m, 3H).

Step f)2-Amino-5-[3-(1,4-difluorobutyl)phenyl]-5-[4-(difluoromethoxy)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one

Using essentially the same procedures described in Example 13, Step e,and Example 1, Step c, and employing1-(3-{[4-(difluoromethoxy)phenyl]ethynyl}phenyl)-1,4-difluorobutane asstarting material, the title product was obtained as a foamy solid, mp54-57° C.; ¹H NMR (400 MHz, DMSO-d₆) δ: 1.61-1.91 (m, 4H), 2.94 (s, 3H),4.34-4.50 (m, 2H), 5.43-5.58 (m, 1H), 6.67 (br s, 2H), 7.06 (d, 2H,J=8.8 Hz), 7.12 (t, 1H, J=74.2 Hz), 7.2 (d, 1H, J=7.4 Hz), 7.28 (d, 1H,J=7.7 Hz), 7.40 (m, 4H). MS (ESI) m/z 424.2 ([M+H])⁺ and MS (ESI) m/z422.2 ([M−H])⁻

EXAMPLE 17 Preparation of2-Amino-5-[4-(difluoromethoxy)phenyl]-5-[3-(3-fluorobut-3-en-1-yl)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one

Step a) 1-Bromo-3-but-3-enylbenzene

A solution of 1.34 gm (3.77 mmol) of methyltriphenylphosphonium bromidein THF at 0° C. was treated dropwise with 2.3 mL of 1.6 M n-BuLi inhexanes (3.77 mmol), stirred at 0° C. for 0.25 h, cooled to −78° C.,treated dropwise with a solution of 3-(3-bromophenyl)propionaldehyde(0.7 gm, 3.28 mmol) in THF, stirred at −78° C. for 1 h, allowed to warmto room temperature, quenched with aqueous NH₄Cl and concentrated underreduced pressure. The resultant residue was taken up in EtOAc, washedsequentially with water and brine, dried over Na₂SO₄ and concentratedunder reduced pressure. Chromatography of this concentrate on silica gelwith a gradient of 0.5% EtOAc-hexanes to 2.0% EtOAc-hexanes gave1-bromo-3-but-3-enylbenzene as an oil, 0.35 gm (50% yield); ¹H NMR (400MHz, CDCl₃) δ: 2.33 (m, 2H), 2.66 (t, 2H, J=7.4 Hz), 4.98 (m, 2H), 5.79(m, 1H), 7.12 (m, 2H), 7.30 (m, 2H).

Step b) 1-Bromo-3-(3-fluoro-4-iodo-butyl)-benzene

A solution of 0.245 gm (1.16 mmol) of 1-bromo-3-but-3-enylbenzene inCH₂Cl₂ at 0° C. was treated with 0.39 gm (1.74 mmol) ofN-iodosuccinimide and 1.05 gm (1.74 mmol) of 50% wt/wttetrabutylammoniumdihydrogen trifluoride in CH₂Cl₂, stirred at 0° C. for2 h, warmed to room temperature over a 1 h period and poured intoCH₂Cl₂. The resultant organic phase was washed sequentially with waterand brine, dried over Na₂SO₄ and concentrated under reduced pressure.Chromatography of the concentrate on silica gel with a gradient ofhexanes to 7.0% EtOAc-hexanes afforded1-bromo-3-(3-fluoro-4-iodo-butyl)-benzene as an oil, 0.40 gm (50%yield); ¹H NMR (400 MHz, CDCl₃) δ: 2.03 (m, 2H), 2.74 (m, 2H), 3.29 (dd,2H, J=5.4, 19.1 Hz), 4.47 (m, 1H), 7.12 (m, 2H), 7.32 (m, 2H).

Step c) 1-Bromo-3-(3-fluorobut-3-enyl)benzene

A solution of 0.405 gm (1.1 mmol) of1-bromo-3-(3-fluoro-4-iodobutyl)-benzene in CH₂Cl₂ was treated with 0.82mL (5.5 mmol) of DBU at room temperature, stirred at room temperaturefor 24 h and poured into EtOAc. The resultant organic phase was washedsequentially with water and brine, dried over Na₂SO₄ and concentratedunder reduced pressure. Chromatography of the concentrate on silica gelwith a gradient of hexanes to 7.0% EtOAc-hexanes gave1-bromo-3-(3-fluorobut-3-enyl)benzene as an oil, 0.20 gm (80% yield); ¹HNMR (400 MHz, CDCl₃) δ: 2.45 (m, 2H), 2.78 (t, 2H, J=7.8 Hz), 3.29 (dd,1H, J=2.8, 50.1 Hz), 4.50 (dd, 1H, J=2.8, 7.3 Hz), 7.12 (m, 2H), 7.32(m, 2H).

Step d)2-Amino-5-[4-(difluoromethoxy)phenyl]-5-[3-(3-fluorobut-3-en-1-yl)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one

Using essentially the same procedure described in Example 1, Steps a, band c, and employing 1-bromo-3-(3-fluorobut-3-enyl)benzene as startingmaterial, the title product was obtained as a yellow-tan foamy solid, mp58-60° C.; ¹H NMR (400 MHz, DMSO-d₆) δ: 2.39 (m, 2H), 2.64 (m, 2H), 2.93(s, 3H), 4.29 (dd, 1H, J=8.8, 52.0 Hz), 4.47 (dd, 1H, J=2.9, 18.2 Hz),7.05 (brs, 2H), 7.12 (t, 1H, J=74.2 Hz), 7.08 (m, 3H), 7.15 (m, 1H),7.25 (m, 1H), 7.40 (m, 2H), 7.54 (m, 1H); MS (ESI) m/z 404.1 ([M+H])⁺and MS (ESI) m/z 402.1 ([M−H])⁻.

EXAMPLE 18 Preparation of2-Amino-5-[3-(4,4-difluorobut-3-en-1-yl)phenyl]-5-[4-(difluoromethoxy)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one

Step a) 3-[3-(4-Difluoromethoxyphenylethynyl)phenyl]propionaldehyde

Using essentially the same procedure described in Example 16, step e,and employing 3-(3-bromophenyl)propionaldehyde in place of1-bromo-3-(1,4-difluorobutyl)benzene afforded3-[3-(4-difluoromethoxy-phenylethynyl)phenyl]propionaldehyde as an oilin 42% yield. This oil was used without further purification in the nextstep.

Step b)1-(3-{[4-(Difluoromethoxy)phenyl]ethynyl}phenyl)-4,4-difluorobut-3-ene

A solution of 0.122 mL (0.86 mmol) of diisopropylamine in THF at −78° C.was treated with 0.54 mL (0.54 mmol) of 1.6 M n-BuLI in hexanes, stirredat −78° C. for 0.5 h, treated dropwise with a solution of 0.22 gm (0.86mmol) of difluoromethyldiphenylphosphine oxide in THF, stirred at −78°C. for 45 min, treated with a solution of3-[3-(4-difluoromethoxyphenylethynyl)phenyl]propionaldehyde 0.17 gm(0.58 mmol) in THF, stirred at −78° C. for 4 h, warmed to roomtemperature, stirred at room temperature for 18 h and diluted withCH₂Cl₂. The organic phase was washed sequentially with water and brine,dried over Na₂SO₄ and concentrated under reduced pressure.Chromatography of this concentrate on silica gel with a gradient ofhexanes to 10% EtOAc-hexanes yielded1-(3-{[4-(difluoromethoxy)phenyl]ethynyl}-phenyl)-4,4-difluorobut-3-eneas an oil, 0.09 gm (52% yield); ¹H NMR (400 MHz, CDCl₃) δ: 2.29 (m, 2H),2.66 (t, 2H, J=7.6 Hz), 4.13 (m, 1H), 6.50 (t, 1H, J=73.6 Hz), 7.07 (d,2H, J=8.8 Hz), 7.13 (m, 1H), 7.26 (d, 1H, J=8.8 Hz), 7.34 (m, 2H), 7.49(dt, 2H, J=2.1, 2.6, 8.3 Hz).

Step c)2-Amino-5-[3-(4,4-difluorobut-3-en-1-yl)phenyl]-5-[4-(difluoromethoxy)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one

Using essentially the same procedure described in Example 1, Steps b andc, and employing1-(3-{[4-(difluoromethoxy)phenyl]ethynyl}phenyl)-4,4-difluorobut-3-eneas starting material, the title compound is obtained as a light yellowsolid, mp 59-62° C.; ¹H NMR (400 MHz, DMSO-d₆) δ: 2.14 (q, 2H, J=7.4Hz), 2.49 (m, 2H), 2.93 (s, 3H), 4.37 (m, 1H), 6.60 (brs, 2H), 7.05 (d,2H, J=8.7 Hz), 7.12 (t, 1H, J=74.2 Hz), 7.18 (m, 2H), 7.21 (m, 2H), 7.40(d, 2H, J=8.7 Hz); MS (ESI) m/z 422.1 ([M+H])⁺ and MS (ESI) m/z 420.1([M−H])⁻.

EXAMPLE 19 Preparation of2-Amino-5-[3-(4,4-difluorobutyl)phenyl]-5-[4-(difluoromethoxy)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one

Step a) 1-Bromo-3-(4,4-difluorobutyl)benzene

A solution of 4-(3-bromophenyl)butyraldehyde (0.6 g, 2.6 mmol) inpentane was treated with a solution diethylaminosulfur trifluride (DAST)(0.38 mL, 2.8 mmol) in pentane, stirred at room temperature for 1 hr,poured into water and extracted with ether. The extracts were combined,washed with brine, dried over magnesium sulfate and concentrated invacuo. The resultant residue was purified by flash chromatography onsilica gel in hexane) to afford 1-bromo-3-(4,4-difluorobutyl)benzene asa clear oil, 0.36 g (54% yield); ¹H NMR (DMSO-d₆) δ 1.7 (m, 4H); 2.6 (t,2H); 6.6 (txd, 1H); 7.2 (m, 2H); 7.38 (d, 1H), 7.39 (s, 1H). massspectrum [(+)ESI] m/z=248 [M−H]⁺.

Step b)2-Amino-5-[3-(4,4-difluorobutyl)phenyl]-5-[4-(difluoromethoxy)-phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one

Using essentially the same procedure described in Example 18, Steps aand c, and employing 1-bromo-3-(4,4-difluorobutyl)-benzene and1-difluoromethoxy-4-ethynylbenzene as reactants, the title compound wasobtained as a white solid, 0.17 g (42% yield), mp 54-57° C.; ¹H NMR(DMSO-d₆) δ 1.6 (m, 2H); 1.8 (m, 2H); 2.5 (t, 2H); 2.95 (s, 3H); 6.0(txd, 1H); 6.6 (b, 2H); 7.1 (m, 4H); 7.4 (d, 2H). MS [(+)ESI] m/z 424[M−H]⁺.

EXAMPLE 20 Preparation of2-Amino-5-[4-(difluoromethoxy)phenyl]-5-[3-(4-hydroxybut-1-yn-1-yl)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one

A mixture of copper iodide (8 mg, 0.04 mmol), bis(benzonitrile)dichloropalladium(II) (23 mg, 0.06 mmol) and anhydrous dioxane under argon wasstirred for 3 min., treated with tri-t-butyl phosphine (10% in hexane)(240 mg, 0.12 mmol), stirred for 5 min. treated with diisopropyl amine(0.33 mL, 2.4 mmol) followed by a solution of2-amino-5-(3-bromophenyl)-5-[4-(difluoromethoxy)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one(0.82 g, 2 mmol) in dioxane and 1-hydroxy-2-propyne (0.47 mL, 0.006mmol). The reaction mixture was heated to 35° C. for 30 min., pouredinto water and extracted with ethyl acetate. The extracts were combined,washed with brine, dried over sodium sulfate and concentrated underreduced pressure. The resultant residue was purified by flashchromatography on silica gel, 1^(st) in ethyl acetate 2^(nd) 5%methanol/ethyl acetate as eluent to afford the title compound as a whitesolid, 0.39 g (48% yield), mp 90-93° C.; ¹H NMR (DMSO-d₆) δ 2.5 ((2H,under DMSO peak); 2.95 (s, 3 H); 3.5 (q, 2 H); 4.8 (t, 1 H); 6.6 (b,2H); 7.1 (d, 2H); 7.15 (t, 2F); 7.2 (m, 2 H); 7.3 (m, 4 H); MS [(+)ESI]m/z=400.2 [M−H]⁺.

EXAMPLE 21 Preparation of2-Amino-5-[4-(difluoromethoxy)phenyl]-5-[3-(4-hydroxybutyl)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one

A mixture of a solution of2-amino-5-[4-(difluoromethoxy)phenyl]-5-[3-(4-hydroxybut-1-yn-1-yl)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one(0.26 g, 0.65 mmol) in ethanol and 5% palladium on charcoal (26 mg) wasplaced on a Paar hydrogenator at 40 psi hydrogen for 8 hrs. The reactionmixture was filtered through a celite pad. The filtrate was concentratedin vacuo. The resultant residue was purified by flash chromatography onsilica gel, 5% methanol/ ethyl acetate as eluent, to give the titleproduct as a white solid, 0.16 g (61% yield), mp 63-66° C.; ¹H NMR(DMSO-d₆) δ 1.4 ((2H, 2H); 1.5 (m, 1 H); 2.5 (2H, under DMSO peak) 2.95(s, 3 H); 3.3 (q, 2 H); 4.3 (t, 1 H); 6.6 (b, 2H); 7.1 (m, 3H); 7.15 (t,2F); 7.2 (m, 3 H); 7.4 (d, 2 H); MS [(+)ESI] m/z=404 [M−H]⁺.

EXAMPLE 22 Preparation of2-Amino-5-[4-(difluoromethoxy)phenyl]-5-[3-(3-methoxyprop-1-yn-1-yl)-phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one

A solution of2-amino-5-(3-bromophenyl)-5-[4-(difluoromethoxy)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one(0.65 g, 1.6 mmol) in pyrrolidine was treated with 3-methoxy-propyne(0.27 mL, 3.2 mmol) followed by tetrakis(triphenylphosphine)palladium(0) (90 mg, 0.08 mmole), heated to 80° C. for 4 hrs, pouredinto water and extracted with ethyl acetate. The extracts were combined,washed sequentially with water and brine, dried over magnesium sulfateand concentrated in vacuo. The resultant residue was purified by flashchromatography on silica gel in ethyl acetate to give the title productas a brown wax, 0.4 g (63% yield), identified by NMR and mass spectralanalyses.

EXAMPLE 23 Preparation of2-Amino-5-[4-(difluoromethoxy)phenyl]-5-{3-[(1Z)-3-methoxyprop-1-en-1-yl]phenyl}-3-methyl-3,5-dihydro-4H-imidazol-4-one

A mixture of a solution of2-amino-5-[4-(difluoromethoxy)phenyl]-5-[3-(3-methoxyprop-1-yn-1-yl)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one(0.1 g, 0.25 mmol) in ethanol (1.5 mL), quinoline (1 drop) and Lindlarcatalyst (24 mg. 10% mol) was placed under a hydrogen filled balloon,stirred for 16 hr filtered through celite. The filtrate was concentratedin vacuo. The resultant residue was purified by flash chromatography onsilica ge,l ethyl acetate as eluent, to afford the title compound as awhite solid, 0.05 g (50% yield), mp 41-44° C.; ¹H NMR (DMSO-d₆) δ 2.95(s, 3H); 3.2 (s, 3H); 4.0 (d, 2H); 5.7 (q, 1H) 6.5 (d, 1H); 6.6 (b, 2H);7.1 (m, 3H); 7.3 (m, 4H); 7.4 (d, 2H); MS [(+)ESI] m/z=402 [M−H]⁺.

EXAMPLE 24 Preparation of2-Amino-5-[4-(difluoromethoxy)phenyl]-5-[3-(3-methoxypropyl)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one

A mixture of an ethanolic solution of2-amino-5-[4-(difluoromethoxy)phenyl]-5-[3-(3-methoxyprop-1-yn-1-yl)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one(0.1 g, 0.25 mmol) and 10% palladium on charcoal (10 mg) was placedunder a hydrogen filled balloon for 16 h and filtered thru celite. Thefiltrate was concentrated to dryness in vacuo. The resultant residue waspurified by flash chromatography on silica gel, ethyl acetate as eluent,to give the title product as a white solid, 0.04 g (40% yield), mp48-50° C.; ¹H NMR (DMSO-d₆) δ 2.4 (m, 2H); 2.95 (s, 3H); 3.2 (s, 3H);3.3 (t, 2H); 6.6 (b, 2H); 7.1 (m, 3H); 7.2 (m, 4H); 7.4 (d, 2H); MS[(+)ESI] m/z=404 [M−H]⁺.

EXAMPLE 25 Preparation of2-Amino-5-[4-(difluoromethoxy)phenyl]-5-[3-(5-fluoropentyl)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one

Step a) 5-(3-Bromophenyl)pentan-1-ol

A mixture of an ethanolic solution of 5-(3-Bromo-phenyl)-pent-4-yn-1-ol(Example 3, step a) (1 g, 4.2 mmol)and platinum oxide (24 mg, 10% mol)was placed on a parr shaker for 4 hrs under 40 psi of hydrogen. Thereaction mixture was filtered through celite. The filtrate wasconcentrated in vacuo. The resultant residu was purified by flashchromatography on silica gel, 1^(st) 10:1 hexane/ ethyl acetate, 2^(nd)2:1 hexane/ethyl acetate as eluent, to give 5-(3-bromophenyl)pentan-1-olas a clear oil, 0.75 g (74% yield); ¹H NMR (DMSO-d₆) δ 1.2 (m, 2H); 1.3(m, 2H); 1.5 (m, 2 H); 3.3 (q, 2H); 4.3 (t, 1 H); 7.2 (m, 2 H); 7.4 (m,2 H) MS [(+)ESI] m/z=243 [M−H]⁺.

Step b) 1-Bromo-3-(5-fluoropentyl)benzene

A solution of 5-(3-bromophenyl)pentan-1-ol (0.63 g, 2.6 mmol) inmethylene chloride at −78° C. was treated with a solution ofdiethylamino sulfur trifluoride (DAST) (0.7 mL, 5.2 mmol) in methylenechloride, allowed to warm to room temperature, stirred for 0.5 h at roomtemperature, poured into water and extracted with ether. The extractswere combined washed sequentially with saturated sodium bicarbonate andwater, dried over magnesium sulfate and concentrated under reducedpressure. The concentrate was purified by flash chromatography on silicagel, 40:1 hexane/ethyl acetate as eluent to give1-bromo-3-(5-fluoropentyl)benzene as a pale yellow oil, 0.4 g (63%yield); ¹H NMR (DMSO-d₆) δ 1.3 (m, 2H); 1.6 (m, 4H); 2.5 (t, 2 H); 4.4(dxt, 2H); 7.2 (m, 2 H); 7.4 (m, 2 H); MS [(+)ESI] m/z=245 [M−H]⁺.

Step c)2-amino-5-[4-(difluoromethoxy)phenyl]-5-[3-(5-fluoropentyl)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one

Using essentially the same procedure described in Example 18, Steps aand c, and employing 1-bromo-3-(5-fluoropentyl)benzene and1-difluoromethoxy-4-ethynylbenzene as reactants, the title compound wasobtained as a white solid, 0.04 g (18% yield); ¹H NMR (DMSO-d₆) δ 1.3(m, 2H); 1.6 (m, 4H); 2.6 (t, 2 H); 2.95 (s, 3H); 4.4 (dxt, 2H); 6.6 (b,2H); 7.0 (m, 3H); 7.2 (m, 4H); 7.4 (d, 2H); MS [(+)ESI] m/z 420 [M−H]⁺.

EXAMPLE 26 Preparation of2-Amino-5-[4-(difluoromethoxy)phenyl]-5-[3-(4-fluorobutyl)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one

Using essentially the same procedure described in Example 25 andemploying 1-bromo-3-(4-fluorobutyl)benzene, the title compound isobtained as a white solid; ¹H NMR (DMSO-d₆) δ 1.6 (m, 4H); 2.5 (m, 2 H);2.95 (s, 3H); 4.4 (dxt, 2H); 6.6 (b, 2H); 7.0 (m, 3H); 7.2 (m, 4H); 7.4(d, 2H); MS [(+)ESI] m/z=406 [M−H]⁺.

EXAMPLE 27 Preparation of2-Amino-5-[4-(difluoromethoxy)phenyl]-5-[3-(6-fluorohexyl)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one

Using essentially the same procedure described in Example 25 andemploying 1-bromo-3-(6-fluorohexyl)benzene, the title compound isobtained as a white solid, ¹H NMR (DMSO-d₆) δ 1.3 (m, 4H); 1.6 (m, 4H);2.5 (m, 2 H); 2.95 (s, 3H); 4.4 (dxt, 2H); 6.6 (b, 2H); 7.0 (m, 3H); 7.2(m, 4H); 7.4 (d, 2H); MS [(+)ESI] m/z 434 [M−H]⁺.

EXAMPLE 28 Preparation of2-Amino-5-[4-(difluoromethoxy)phenyl]-5-[3-(6-fluorohexyl)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one

Step a) 1-bromo-3-(4-methoxybutyl)benzene

A mixture of sodium hydride [60% in oil] (130, mg, 3.3 mmol) and THF wascooled to −5° C., was treated via a syringe over a 1 min. period with asolution of 4-(3-romophenyl)butan-1-ol (0.7 g, 3.0 mmol) in THF, warmedto room temperature and stirred at room temperature for 0.5 h, treatedwith methyl iodide (4.6 g, 35 mmol), stirred for 2 h, poured intosaturated ammonium chloride and extracted with ether. The extracts werecombined, washed with brine, dried over magnesium sulfate adnconcentrated in vacuo. The resultant residue was purified by flashchromatography on silica gel, 40:1 hexane/ethyl acetate as eluent, toafford 1-bromo-3-(4-methoxybutyl)benzene as a clear oil, 0.38 g (51%yield); ¹H NMR (DMSO-d₆) δ 1.4 (m, 2H); 1.5 (m, 2H); 2.5 (t, 2 H); 3.2(s, 3H); 3.3 (t, 2H); 7.2 (m, 2H); 7.4 (m, 2H); MS [(+)ESI] m/z=244[M−H]⁺.

Step b)2-amino-5-[4-(difluoromethoxy)phenyl]-5-[3-(4-methoxybutyl)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one

Using essentially the same procedure described in Example 18, Steps aand c, and employing 1-bromo-3-(4-methoxybutyl)benzene and1-difluoromethoxy-4-ethynylbenzene as reactants, the title compound wasobtained as a white solid, mp 36-39° C.; ¹H NMR (DMSO-d₆) δ 1.4 (m, 4H);2.5 (m, 2 H); 2.95 (s, 3H); 3.2 (s, 3H); 3.3 (t, 2H); 6.6 (b, 2H); 7.0(m, 3H); 7.2 (m, 4H); 7.4 (d, 2H); MS [(+)ESI] m/z 418 [M−H]⁺.

EXAMPLE 29 Preparation of3-{2-Amino-4-[4-(difluoromethoxy)phenyl]-1-methyl-5-oxo-4,5-dihydro-1H-imidazol-4-yl}-N-propylbenzamide

Step a) 3-Bromo-N-propyl-benzamide

A mixture of N-propyl amine (0.33 mL, 4.1 mmol) and triethylamine (0.83mL, 5.8 mmol) in methylene chloride was cooled to −5° C., treated with3-bromobenzoyl chloride (1 g, 4.5 mmol), warmed to room temperature,stirred at room temperature for 1 h, poured into aqueous sodiumbicarbonate and extracted with methylene chloride. The extracts werecombined, washed sequentially with water and brine, dried over magnesiumsulfate and concentrated under reduced pressure. The resultant residuewas purified by flash chromatography on silica gel, 2:1 hexane/ethylacetate as eluent, to give 3-bromo-N-propyl-benzamide as a white solid,0.74 g (67% yield); ¹H NMR (DMSO-d₆) δ 0.8 (t, 3H); 1.5 (m, 2H); 3.2 (t,2H); 7.4 (t, 1H); 7.6 (d, 1H), 7.8 (d, 1H); 7.9 (s, 1H); 8.5 (b, 1H); MS[(+)ESI] m/z 242[M−H]⁺.

Step b)3-{2-amino-4-[4-(difluoromethoxy)phenyl]-1-methyl-5-oxo-4,5-dihydro-1H-imidazol-4-yl}-N-propylbenzamide

Using essentially the same procedure described in Example 18, Steps aand c, and employing 3-bromo-N-propyl-benzamide and1-difluoromethoxy-4-ethynylbenzene as reactants, the title compound wasobtained as a white solid, mp 93-96° C. ¹H NMR (DMSO-d₆) δ 0.8 (t, 3H);1.4 (m, 2H); 2.95 (s, 3H); 3.2 (t, 2H); 6.7 (b, 2H); 7.1 (d, 2H); 7.3(m, 1H); 7.4 (d, 2H); 7.5 (d, 1H); 7.6 (d, 1H), 7.7 (s, 1H); 8.4 (b,1H); MS [(+)ESI] m/z 417 [M−H]⁺.

EXAMPLE 30 Preparation2-Amino-5-[4-(difluoromethoxy)phenyl]-5-{3-[(2-fluoroethoxy)methyl]phenyl}-3-methyl-3,5-dihydro-4H-imidazol-4-one

Step a) 1-Bromo-3-(2-fluoroethoxymethyl)benzene

A mixture of sodium hydride [60% in oil] (343, mg, 8.6 mmol) and THF at−5° C. was treated via a syringe with a solution of 2-fluoroethanol inTHF over a 1 min. period, stirred for 2 min., warmed to roomtemperature, stirred for 15 min. at room temperature, treated with3-bromobenzylbromide (2.5 g, 11.7 mmol), stirred for 1 h, poured intosaturated ammonium chloride and extracted with ether. The extracts werecombined, washed sequentially with water and brine, dried over magnesiumsulfate and concentrated under reduced pressure. The residue waspurified by flash chromatography on silica gel, 20:1 hexane/ ethylacetate as eluent, to afford 1-bromo-3-(2-fluoroethoxymethyl)benzene asa yellow oil, 1 g (58% yield), ¹H NMR (DMSO-d₆) δ 3.6 (dxt, 2H); 4.5(dxt, 2H); 4.4 (s, 2 H); 7.3 (m, 2H); 7.5 (m, 2H); MS [(+)ESI] m/z 219[M−H]⁺.

Step b)2-Amino-5-[4-(difluoromethoxy)phenyl]-5-{3-[(2-fluoroethoxy)methyl]-phenyl}-3-methyl-3,5-dihydro-4H-imidazol-4-one

Using essentially the same procedure described in Example 18, Steps aand c, and employing 1-bromo-3-(2-fluoroethoxymethyl)benzene and1-difluoromethoxy-4-ethynylbenzene as reactants, the title compound wasobtained as a white solid, mp 40-43° C.; ¹H NMR (DMSO-d₆) δ 2.95 (s,3H); 3.6 (dxt, 2H); 4.4 (m, 3H); 4.6 (t, 1H); 6.7 (b, 2H); 7.1 (d, 2H);7.2 (m, 1H); 7.3 (m, 1H); 7.4 (m, 1H); 7.5 (m, 3H); MS [(+)ESI] m/z 408[M−H]⁺.

EXAMPLES 31-39 Preparation2-Amino-5-[4-(difluoromethoxy)phenyl]-5-[3-(alkoxymethyl)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one

Using essentially the same procedure described in Example 30 andemploying the desired alcohol in Step a, the compounds shown on Table Iwere obtained and identified by NMR and mass spectral analyses.

TABLE I

Ex. mp No. R ° C. [M + H]⁺ 31 CH₂CH₂CF₃ 46-48 458 32 CH₃ 70-72 376 33CH₂CH₂CH₂CH₃ 37-39 418 34

47-50 416 35 CH₂CH₃ 45-48 390 36 CH₂CH₂CH₃ 40-43 404 37 CH(CH₂F)CH₂F46-50 440 38 CH₂CF₃ 50-52 441 39 CH₂CF₂CHF₂ 48-50 476

EXAMPLE 40 Preparation of2-Amino-5-[4-(difluoromethoxy)phenyl]-5-{3-[(1E)-6-methoxy-hex-1-en-1-yl]-phenyl}-3-methyl-3,5-dihydro-4H-imidazol-4-one

Step a) (E)-6-Methoxy-hex-1-enylboronic acid

A mixture of methylhexynyl ether (7.2 mmol), 9-BBN 0.5M in THF (1.8 ml,0.9 mmol) and catecholborane (1.21 g, 10.1 mmol) is heated in a pressuretube at 100° C. for 16 h, quenched with pH 7 phosphate buffer, stirredfor 2 h, and extracted with ether. The combined extracts are dried overMgSO₄ and concentrated in vacuo. The resultant residue is purified byflash chromatography to obtain (E)-6-methoxy-hex-1-enylboronic acid,identified by NMR and mass spectral analyses. (¹H-NMR 300 MHz,CDCl3+D2O): 6.52 (dt, 1H); 5.44 (dt, 1H); 3.40 (t, 2H); 3.35 (s, 3H);2.21 (ddt, 2H); 1.68-1.45 (m, 4H).

Step b)2-Amino-5-[4-(difluoromethoxy)phenyl]-5-{3-[(1E)-6-methoxy-hex-1-en-1-yl]-phenyl}-3-methyl-3,5-dihydro-4H-imidazol-4-one

A degassed solution of2-amino-5-(3-bromophenyl)-5-[4-(difluoromethoxy)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one(200 mg, 0.488 mmol) and (E)-6-methoxy-hex-1-enylboronic acid (0.537mmol) in 1 ml of 2 M K₂CO₃ and 2.5 ml of DME is treated withPd(CH₃CN)₂Cl₂ (20 mg, 5%), the mixture heated at 95° C. under a nitrogenatmosphere for 16 h, diluted with water and extracted with CH₂Cl₂. Theextracts are combined, dried over MgSO₄ and concentrated in vacuo. Theresultant residue is purified on a silica gel cartridge and then bypreparative HPLC to afford the title compound, 121 mg (56% yield),identified by NMR and mass spectral analyses. (¹H-NMR 300 MHz, CDCl3):7.49 (d, 2H); 7.42 (s br, 1H); 7.27 (m, 5H); 7.06 (d, 2H); 6.49 (dd,1H); 6.36 (d, 1H); 6.20 (dt, 1H); 3.41 (t, 2H); 3.35 (s, 3H); 3.12 (s,3H); 2.22 (dt, 2H); 1.69-1.47 (m, 4H). MS [M+H]⁺ 444.4

EXAMPLE 41 Preparation of2-Amino-5-[4-(difluoromethoxy)phenyl]-5-{3-[(1E)-5-hydroxy-pent-1-en-1-yl]-phenyl}-3-methyl-3,5-dihydro-4H-imidazol-4-one

Step a) t-Butylpent-4-ynyloxy diphenyl silane

A mixture of pentynol (8.0 g, 95 mmol), t-butyldiphenylsilylchloride (28g, 114 mmol) and Et₃N (14 g, 138 mmol) in CH₂Cl₂ is stirred at roomtemperature for 16 h, treated with 1M K₂CO₃ and extracted with CH₂Cl₂.The combined extracts are dried over MgSO₄ and concentrated in vacuo.The residue is purified by filtration on a silica pad to obtain 30 g oft-butylpent-4-ynyloxy diphenyl silane (yield: 98%

Step b)2-Amino-5-[4-(difluoromethoxy)phenyl]-5-{3-[(1E)-5-hydroxy-pent-1-en-1-yl]-phenyl}-3-methyl-3,5-dihydro-4H-imidazol-4-one

Using essentially the same procedure described in Example 40 andemploying t-butylpent-4-ynyloxy diphenyl silane, the silyl ether of thetitle compound is obtained. A solution of the silyl ether (635 mg, 0.97mmol) in THF is treated with 1M TBAF in THF (1 ml, 1 mmol), stirred for16 h, diluted with water and extracted with CH₂Cl₂. The combinedextracts are dried over MgSO₄ and concentrated in vacuo. The resultantresidue is purified by a silica cartridge, by preparative HPLC and bySCX cartridge (to eliminate all residual TBAF) to afford the titleproduct as a white solid, 59 mg (15% yield), identified by NMR and massspectral analyses. (¹H-NMR 300 MHz, DMSO): 7.47(d, 2H); 7.34-7.14(m,4H); 7.16(t, 1H); 7.11(d, 2H); 6.68(s br, 2H); 6.35(d, 1H); 6.19(dt,1H); 4.40(t, 1H); 3.42(dt, 2H); 2.98(s, 3H); 2.19(m, 2H); 1.57(m, 2H).MS [M+H]⁺ 416.1.

EXAMPLES 42-49 Preparation of2-Amino-5-[4-(difluoromethoxy)phenyl]-5-(3-alkenylphenyl)-3-methyl-3,5-dihydro-4H-imidazol-4-oneCompounds

Using essentially the same procedures described in Examples 40 and 41and employing the desired alkyne in Step a, the compounds shown on TableII were obtained and identified by NMR and mass spectral analyses.

TABLE II

Ex. No. R R5 [M + H]⁺ 42 CH₂CH₂OCH₃ H 430.2 43 OCH₃ H 402.1 44 CH₂OCH₃ H416.1 45 CH₂OH H 402.1 46 CH₂F H 404.1 47 CH₂CH₂F H 408.1 48 CH₂F F422.01 49 CHF₂ H 422.1

EXAMPLE 50 Preparation of2-Amino-5-[4-(difluoromethoxy)phenyl]-5-{3-[2-(methoxymethyl)cyclopropyl]phenyl}-3-methyl-3,5-dihydro-4H-imidazol-4-one

A 1M solution of diethyl zinc (4.92 ml, 4.92 mmol) in dry CH₂Cl₂ at 0°C. is treated very slowly with a solution of CF₃CO₂H (0.56 g, 4.92 mmol)in dry CH₂Cl₂, stirred for 20 min, treated dropwise with a solution ofCH₂I₂ (0.66 g, 2.46 mmol) in dry CH₂Cl₂, stirred for 20 min, treatedwith a solution of2-amino-5-[4-(difluoromethoxy)phenyl]-5-{3-[(1E)-3-methoxyprop-1-en-1-yl]phenyl}-3-methyl-3,5-dihydro-4H-imidazol-4-one(197 mg, 0.492 mmol) in dry CH₂Cl₂, allowed to come to room temperature,stirred for 2 h at room temperature, quenched with aqueous NH₄Cl andextracted with CH₂Cl₂. The combined extracts are dried over MgSO₄ andconcentrated in vacuo. The resultant residue is purified by SCXcartridge and preparative HPLC to give the title compound as a whitesolid, 32 mg (16% yield), identified by NMR and mass spectral analyses.(¹H-NMR 300 MHz, DMSO): 7.46(d, 2H); 7.24-7.13(m, 3H); 7.16(t, 1H);7.10(d, 2H); 6.88(m, 1H); 6.64(s br, 2H); 3.44-3.34(m, 2H); 3.24(m, 1H);3.23(s, 3H); 2.97(s, 3H); 1.76(m, 1H); 0.90-0.76(m, 2H). MS [M+H]⁺ 416.1

EXAMPLE 51 Preparation of2-Amino-5-[4-(difluoromethoxy)phenyl]-5-{3-[2-(2-methoxyethyl)cyclopropyl]phenyl}-3-methyl-3,5-dihydro-4H-imidazol-4-one

Using essentially the same procedure described in Example 50 andemploying2-amino-5-[4-(difluoromethoxy)-phenyl]-5-{3-[(1E)-4-methoxybut-1-en-1-yl]phenyl}-3-methyl-3,5-dihydro-4H-imidazol-4-oneas starting material, the title product is obtained as a white solid andidentified by NMR and mass spectral analyses. ¹HNMR: (DMSO d₆) δ 7.46(d,2H); 7.22-7.13(m, 3H); 7.16(dd, 1H); 7.10(d, 2H); 6.87(d br, 1H); 6.64(sbr, 2H); 3.38(t, 2H); 3.22(s, 3H); 2.98(s, 3H); 1.68-1.45(m, 3H);0.97(m, 1H); 0.76(m, 2H). MS [M+H]⁺ 430.1

EXAMPLE 52 Preparation of5-(3-Acetylphenyl)-2-amino-5-[4-(difluoromethoxy)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one

A mixture of2-amino-5-(3-bromophenyl)-5-[4-(difluoromethoxy)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one(1.50 g, 3.66mmol), 1,3-bis(diphenylphosphino)propane (DPPP) (0.377 g,0.915 mmol), K₂CO₃ (0.606 g, 4.39 mmol), Pd(OAc)₂ (82 mg, 0.37 mmol) andn-butylvinylether (1.47 g, 14.6 mmol) in DMF/water (8 ml/0.8 ml) isheated in a microwave oven for 1 h at 120° C., cooled to roomtemperature, treated cautiously with 15 ml of 5% HCl, stirred at roomtemperature for 1 h, diluted with water, basified with aqueous K₂CO₃ andextracted with ethyl acetate. The extracts are combined, dried overMgSO4 and concentrated in vacuo to give a residue. The residue ispurified by SCX cartridge to give the title compound, 1.20 g (88%yield), identified by NMR and mass spectral analyses. ¹H NMR (300MHz,CDCl₃) ppm 8.11 (t, 1 H), 7.87 (dt, 1 H), 7.72-7.80 (m, 1 H), 7.52(d, 2 H), 7.44 (t, 1 H), 7.08 (d, 2 H), 6.49 (t, 1 H), 3.15 (s, 3 H),2.59 (s, 3 H). MS [M+H]⁺ 374.1.

EXAMPLE 53 Preparation of2-Amino-5-[4-(difluoromethoxy)phenyl]-5-[3-(3-hydroxyhex-4-yn-1-yl)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one

Step a)2-Amino-5-[4-(difluoromethoxy)phenyl]-5-[3-(3-hydroxyprop-1-yn-1-yl)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one(1)

A mixture of2-amino-5-(3-bromophenyl)-5-[4-(difluoromethoxy)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one(2.4 g, 5.85 mmol), 3-hydroxy-1-propyne (3.27 g, 58.5 mmol) andPd(PPh₃)₄ (670 mg, 0.585 mmol) in pyrrolidine is heated at 70° C. undera nitrogen atmosphere for 16 h, diluted with water and extracted withCH₂Cl₂. The extracts are combined, dried over MgSO₄ and concentrated invacuo to give a residue. The residue is purified by chromatography on asilica cartridge, to give2-amino-5-[4-(difluoromethoxy)phenyl]-5-[3-(3-hydroxyprop-1-yn-1-yl)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one,1 g (45% yield), identified by NMR and mass spectral analyses.

Step b)2-Amino-5-[4-(difluoromethoxy)phenyl]-5-[3-(3-hydroxypropyl)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one(2)

A mixture of an ethanolic solution of 1 (1 g, 2.6mmol) and PtO₂ (50 mg,10%) is hydrogenated at 15 psi on a Parr hydrogenator for 4 h andfiltered through celite. The filtrate is concentrated to dryness underreduced pressure to afford2-amino-5-[4-(difluoromethoxy)phenyl]-5-[3-(3-hydroxypropyl)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one,830 mg, identified by NMR and mass spectral analyses.

Step c) Compound 3

A solution of 2 (480 mg) in THF under nitrogen is treated with DMAP (150mg, 1.23 mmol) and Boc₂O (938 mg, 4.3 mmol), stirred for 2 h, dilutedwith water and extracted CH₂Cl₂. The extracts are combined, dried overMgSO₄ and concentrated in vacuo to give a residue. The residue isdissolved in 10 ml of MeOH and 30% aqueous NaOH (400 μl, 3 eq), stirredfor 16 h at room temperature, diluted with brine and extracted withCH₂Cl₂. The extracts are combined, dried over MgSO₄ and concentrated invacuo to give a residue. Purification of this residue by flashchromatography affords the protected2-amino-5-[4-(difluoromethoxy)phenyl]-5-[3-(3-hydroxypropyl)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-onecompound, 265 mg (yield: 44%). This compound (265 mg, 0.542 mmol) isdissolved in dry CH₂Cl₂, treated with Dess-Martin's periodinane (276 mg,0.650 mmol), stirred for 2 h, washed with water and brine, dried overMgSO₄ and evaporated to dryness. The resultant residue is purified on asilica cartridge to afford compound 3,170 mg (yield: 64%), identified byNMR and mass spectral analyses.

Step d)2-Amino-5-[4-(difluoromethoxy)phenyl]-5-[3-(3-hydroxyhex-4-yn-1-yl)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one

A solution of 3 (80 mg, 0.164 mmol) in dry THF under nitrogen at −70° C.is treated with the Grignard reagent 4 (656 μl, 0.328 mmol), allowed tocome to room temperature, stirred for 2 h at room temperature, dilutedwith water and extracted with CH₂Cl₂. The extracts are combined, driedover MgSO₄ and concentrated in vacuo to give a residue. This residue (50mg) is dispersed in CH₂Cl₂, treated with trifluoroacetic acid (215 mg,1.9 mmol), stirred for 16 h, washed with aqueous K₂CO₃, dried over MgSO₄and evaporated under reduced pressure. The resultant residue is purifiedby preparative HPLC to give the title product, 15 mg, identified by NMRand mass spectral analyses. ¹H NMR (1H DMSO): 7.44(d, 2H); 7.29-7.07(m,6H); 7.19(dd, 1H); 5.20(d, 1H); 4.13(m, 1H); 3.03(s, 3H); 2.62(m, 2H);1.79(d, 3H); 1.74(m, 2H). MS [M+H]⁺ 428.1.

EXAMPLE 54 Preparation of2-Amino-5-[4-(difluoromethoxy)phenyl]-5-[3-(3-fluoroprop-1-yn-1-yl)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one

A solution of2-mino-5-[4-(difluoromethoxy)phenyl]-5-[3-(3-hydroxyprop-1-yn-1-yl)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one(300 mg, 0.779 mmol) in dry CH₂Cl₂ under nitrogen at −40° C. was treateddropwise with DAST (252 mg, 1.56 mmol), stirred at −40° C. for 1 h,allowed to warm to room temperature, stirred at room temperature for 16h; diluted with water, stirred for 30 min. and extracted with CH₂Cl₂.The extracts are combined, dried over MgSO4 and concentrated in vacuo togive a residue. The residue is repeatedly purified by preparative HPLCto afford the title product, 23 mg (8% yield), LC-MS purity: 98%),identified by NMR and mass spectral analyses. 1H NMR (300 MHz, CDCl₃)ppm 7.60 (s, 1 H), 7.47 (s, 3 H), 7.32-7.38 (m, 1 H), 7.22-7.28 (m, 1H), 7.04 (d, 2 H), 6.47 (t, 1H), 5.14 (d, 2 H), 3.10 (s, 3 H). MS [M+H]⁺388.1.

EXAMPLES 55-57 Preparation of2-Amino-5-[4-(difluoromethoxy)phenyl]-5-[3-(3-substituted)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-oneCompounds

Using essentially the same procedures described in Example 14, Steps f,g and h, and employing the desired halobenzene, the compounds shown inTable III were obtained and identified by NMR and mass spectralanalyses.

TABLE III

Ex. mp No. R4 ° C. [M + H]⁺ 55 CH₂CH₂F 60-63 378 56 COCH₂CH₂CH₂CH₂F —434 57 COCH₂CH₂CH₂F 78-82 420

EXAMPLE 58 Preparation of2-Amino-5-[4-(difluoromethoxy)phenyl]-5-(3hydroxyphenyl)-3-methyl-3,5-dihydro-4H-imidazol-4-one

Step a) 3-((4-(Difluoromethoxy)phenyl)ethynyl)phenol

A solution of 4-(difluoromethoxy)phenyl iodide (4.70 g) in deoxygenateddimethylformamide was treated with trans-dichlorobis(triphenylphosphine)palladium(II) (244 mg) and copper(II) iodide 66 mg) followed bytriethylamine (7.52 mL), stirred under a nitrogen atmosphere for 5min.,treated with 3-hydroxyphenyl acetylene (2.467 g), stirred under nitrogenatmosphere for 16 h, poured into ethyl acetate and was washed with 0.05N HCl and water. The organic phase was dried over MgSO₄ and concentratedin vacuo. The residue was chromatographed, silica gel, 40% ethylacetate/hexane as eluent, to afford3-((4-(difluoromethoxy)phenyl)ethynyl)phenol as a tan solid, 5.40 g; ¹HNMR (DMSO-d6): δ 9.64 (s, 1H), 7.56 (d, J=8.8 Hz, 2H), 7.27 (t, J=73.7Hz, 1H), 7.17 (d, J=8.8 Hz, 2H), 7.16 (m, 1H), 6.94 (m, 1H), 6.86 (m,1H), and 6.77 (m, 1H); MS (ES neg) m/z 260.

Step b)1-(4-(Difluoromethoxy)phenyl)-2-(3-hydroxyphenyl)ethane-1,2-dione

A mixture of 3-((4-(difluoromethoxy)phenyl)ethynyl)phenol (5.0 g) anddichlorobis(acetonitrile)palladium (II) (0.50 g) and dimethylsulfoxidewas heated at 140° for 4 h, cooled to room temperature, poured intowater, stirred well for 10 min. and extracted with chloroform. Thecombined extracts were dried over MgSO₄ and evaporated to a dark oil.The oil was purified by flash chromatography (silica gel) using stepgradient elution (10% ethyl acetate/hexane to 20% ethyl acetate/hexaneto give1-(4-(difluoromethoxy)phenyl)-2-(3-hydroxyphenyl)ethane-1,2-dione as alight yellow waxy solid, 2.75 g; ¹H NMR (DMSO-d6): δ 10.02 (s, 1H), 7.95(d, J=8.9 Hz, 2H), 7.41 (t, J=73.0 Hz, 1H), 7.38 (m, 1H), 7.34 (d, J=8.9Hz, 2H), 7.25 (m, 2H), and 7.12 (m, 1H); MS (ES neg) m/z 292.

Step c)2-Amino-5-[4-(difluoromethoxy)phenyl]-5-(3-hydroxyphenyl)-3-methyl-3,5-dihydro-4H-imidazol-4-one

A mixture of1-(4-(difluoromethoxy)phenyl)-2-(3-hydroxyphenyl)ethane-1,2-dione (2.75g), N-methylguanidine hydrochloride (1.237 g) and sodium carbonate (2.20g) in ethanol was heated at 85° C. for 8 h, cooled to room temperatureand evaporated in vacuo. The resultant residue was partitioned betweenwater and chloroform. The organic phase was separated, dried over Na₂SO₄and evaporated to a light brown oil. The oil was purified by flashchromatography (silica gel) using step gradient elution (100% chloroformto 15% methanol/chloroform) to afford the title compound as a whitefoamy glass, 2.20 g; ¹H NMR (DMSO-d6): δ 9.24 (bs, 1H), 7.42 (d, J=8.8Hz, 2H), 7.12 (t, J=74.3 Hz, 1H), 7.06 (d, J=8.8 Hz, 2H), 7.02 (m, 1H),6.80 (m, 2H), 6.57 (bs, 2H), and 6.56 (m, 1H); MS (APPI) m/z 348.

EXAMPLE 59 Preparation of2-Amino-5-[4-(difluoromethoxy)phenyl]-5-[3-(3-fluoropropox-1-yl)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one

A mixture of2-amino-5-[4-(difluoromethoxy)phenyl]-5-(3-hydroxyphenyl)-3-methyl-3,5-dihydro-4H-imidazol-4-one(197 mg), 1-iodo-3-fluoropropane (127 mg), and cesium carbonate (240 mg)in dry DMF was stirred at room temperature under nitrogen atmosphere for16 h, diluted with chloroform, stirred for 5 min. and filtered through aglass fibre 3.1 μm syringe filter. The filtrate was evaporated, Theresultant residue was purified by HPLC; CN bonded phase prep column,gradient elution (80% A/20% B to 20% A/80% B, A=hexane; B=(20%methanol/80% dichloromethane) to afford a clear oil. The oil wascrystallized from warm ethyl acetate/hexane to give the title compoundas white crystals, mp 161-162° C.; identified by NMR and mass spectralanalyses. MS (APPI) m/z 408;

EXAMPLE 60 Preparation of2-Amino-5-[4-(difluoromethoxy)phenyl]-5-(4-fluoro-3-hydroxyphenyl)-3-methyl-3,5-dihydro-4H-imidazol-4-one

Using essentially the same procedure described in Example 17, step d,and employing 5-bromo-2-fluorophenol as starting material, the titlecompound was obtained and identified by NMR and mass spectral analyses.¹H NMR (DMSO-d6): δ 9.7 (bs, 1H), 7.39 (d, J=8.8 Hz, 2H), 7.12 (t,J=74.1 Hz, 1H), 7.06 (d, J=8.8 Hz, 2H), 7.01 (m, 2H), 6.78 (m, 1H), 6.62(bs, 2H), and 2.93 (s, 3H); MS (ES pos) m/z 365.

EXAMPLES 61-78 Preparation of2-Amino-5-[4-(difluoromethoxy)phenyl]-5-(alkoxyphenyl)-3-methyl-3,5-dihydro-4H-imidazol-4-oneCompounds

Using essentially the same procedure described in Example 59 andemploying the desired alkyl halide and appropriate2-amino-5-[4-(difluoromethoxy)phenyl]-5-(hydroxyphenyl)-3-methyl-3,5-dihydro-4H-imidazol-4-onesubstrate, the compounds shown in Table IV are obtained and identifiedby NMR and mass spectral analyses.

TABLE IV

Ex. mp No. R R5 ° C. m/z 61

H 151-152 402 62 CH₂CH₂CH₂CF₃ H 82-85 458 63 CH₂CHF₂ H 158-159 412 64CH₂CH₂CH₂CH₂F H 139-140 422 65 CH₂CH₂CH₂OC₆H₅ H foam 482 66 CH₂CH₂CH₂CNH foam 415 67 CH₂CH₂CHF₂ F foam 424.2 68

F foam 416.2 69 CH₂CH₂CH₂CH₂F F foam 438.2 70 CH₂CHF₂ F foam 428.1 71CH₂CH₂CH═CH₂ H foam 72 CH₂CH₂CH═CH₂ F 73 CH₂CH₂CH₂CH═CH₂ H 74(R)-CH₂(CH₃)CH₂CH═CH₂ H 75 (S)-CH₂(CH₃)CH₂CH═CH₂ H 76 CH₂═CHCH₂(CH₃)CH₂H 77 CH₃C(═CH₂)CH₂CH₂ H 78 CH₂═CHCH₂ H

EXAMPLE 79 Preparation of(5R)-2-Amino-5-[4-(difluoromethoxy)phenyl]-5-[4-fluoro-3-(3-fluoropropox-1-yl)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one(A) and(5S)-2-Amino-5-[4-(difluoromethoxy)phenyl]-5-[4-fluoro-3-(3-fluoropropox-1-yl)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one(B)

A racemic mixture of2-amino-5-[4-(difluoromethoxy)phenyl]-5-[4-fluoro-3-(3-fluoropropox-1-yl)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-onewas separated by chiral HPLC using column type Chiralcel AD, 5×50 cm;the mobile phase was 14% ethanol in hexane with 0.1% diethylamine at 95mL/min to obtain the title R-isomer (A) as a foam, identified by NMR andmass spectral analyses; [α]D²⁵=−14.00° (1% EtOH); MS (ES) m/z 424.1; andthe title S-isomer (B) as a foam, identified by NMR and mass spectralanalyses; [α]D²⁵=+15.00° (1% EtOH); MS (ES) m/z 424.1.

EXAMPLE 80 Preparation of(5R)-2-Amino-5-[3-(2,2-difluoroethoxy)-4-fluorophenyl]-5-[4-(difluoromethoxy)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one(A) and(5S)-2-Amino-5-[3-(2,2-difluoroethoxy)-4-fluorophenyl]-5-[4-(difluoromethoxy)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one(B)

A racemic mixture of2-amino-5-[3-(2,2-difluoroethoxy)-4-fluorophenyl]-5-[4-(difluoromethoxy)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-onewas separated by chiral HPLC using column type Chiralpak AD-H, 2×25 cm;the mobile phase was 15% ethanol in hexane with 0.1% diethylamine, toobtain the title R-isomer (A) as a glass, identified by NMR and massspectral analyses; MS (ES) m/z 428.1; and the title S-isomer (B) as afoam, identified by NMR and mass spectral analyses; [α]D²⁵=+15.2° (1%EtOH); MS (ES) m/z 428.1.

EXAMPLE 81 Preparation of2-Amino-5-{3-[(4,4-difluorobut-3-en-1-yl)oxy]phenyl}-5-[4-(difluoromethoxy)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one

Step a)1-(4,4-Difluorobut-3-enyloxy)-3-((4-(difluoromethoxy)phenyl)ethynyl)benzene

A mixture of 3-((4-(difluoromethoxy)phenyl)ethynyl)phenol (900 mg),potassium carbonate (636 mg), Aliquat 336 (4 drops), sodium iodide(catalytic) and 4-bromo-1,1-difluoro-1-butene (591 μL) in methyl ethylketone was placed in a pressure vessel, heated at 80° C. for 15 h,cooled to room temperature, diluted with dichloromethane and filtered.The filtrate was concentrated in vacuo. The resultant residue waspurified by flash chromatography (silica gel, eluant: 2.5% ethylacetate/hexane to afford1-(4,4-difluorobut-3-enyloxy)-3-((4-(difluoromethoxy)phenyl)ethynyl)benzene,560 mg (46.2% yield); ¹H NMR (chloroform-d1): δ 7.51 (d, J=8.8 Hz, 2H),7.24 (m, 1H), 7.10 (m, 1H), 7.08 (d, J=8.8 Hz, 2H), 7.03 (m, 1H), 6.87(m, 1H), 6.52 (t, J=73.5 Hz, 1H), 4.32 (m, 1H), 3.97 (t, J=6.4 Hz, 2H)and 2.47 (m, J=6.4 Hz, 2H); MS (ES pos) m/z 350.

Step b)2-Amino-5-{3-[(4,4-difluorobut-3-en-1-yl)oxy]phenyl}-5-[4-(difluoromethoxy)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one

Using essentially the same procedure described in Example 1, steps b andc, and employing1-(4,4-difluorobut-3-enyloxy)-3-((4-(difluoromethoxy)phenyl)ethynyl)benzeneas starting material, the title compound was obtained as a white solid,mp 127-128° C., identified by NMR and mass spectral analyses. MS (ES)m/z 436.1.

EXAMPLE 82 Preparation of2-Amino-5-{3-[(4,4-difluorobut-3-en-1-yl)oxy]-4-fluorophenyl}-5-[4-(difluoromethoxy)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one

Step a) 4-bromo-2-(4,4-difluorobut-3-enyloxy)-1-fluorobenzene

A mixture of 2-fluoro-5-bromophenol (2.40 g), potassium carbonate (2.31m), Aliquat 336 (5 drops), sodium iodide (catalytic) and4-bromo-1,1-difluoro-1-butene (1.79 mL) in methyl ethyl ketone wasplaced in a pressure vessel and heated in a 82° oil bath for 15 hours.The reaction mixture was cooled, diluted with dichloromethane, filteredand evaporated in vacuo. The resultant residue was purified by flashchromatography (silica gel, eluant: 2.5% ethyl acetate/hexane to afford4-bromo-2-(4,4-difluorobut-3-enyloxy)-1-fluorobenzene, 2.23 g (63%yield), identified by NMR analysis.

Step b)2-amino-5-{3-[(4,4-difluorobut-3-en-1-yl)oxy]-4-fluorophenyl}-5-[4-(difluoromethoxy)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one

Using essentially the same procedure described in Example 60 andemploying 4-bromo-2-(4,4-difluorobut-3-enyloxy)-1-fluorobenzene asstarting material, the title compound was obtained as an off-whitesolid, 700 mg (68% yield), mp 139-140° C., identified by NMR and massspectral analyses. MS (ES) m/z 456.1;

EXAMPLE 83 Preparation of2-Amino-5-[4-(difluoromethoxy)phenyl]-5-(4-flroro-3-pent-4-en-1-yl)-3-methyl-3,5-dihydro-4H-imidazol-4-one

Step a) Preparation of 1-fluoro-4-iodo-2-pent-4-en-1-ylbenzene

A stirred solution of 2-fluoro-5-iodo-benzaldehyde (0.714 g, 2.86 mmol)in dry THF at −78° C. under nitrogen was treated over 10 min with 0.5 M3-butenyl magnesium bromide in THF (6.85 mL, 3.43 mmol), stirred for 0.5h, allowed to warm to −30° C. over 1 h, quenched with saturated ammoniumchloride, diluted with water and extracted with ethyl acetate. Theextracts were combined, dried over MgSO₄ and concentrated in vacuo.Purification of the resultant residue by flash chromatography (5% to 10%ethyl acetate/petroleum ether) gave1-(2-fluoro-5-iodo-phenyl)pent-4-en-1-ol as a clear oil, 565 mg (65%yield). A portion of this oil (0.25 g, 0.82 mmol) was dissolved in drymethylene chloride, cooled to 0° C., treated with boron triflourideetherate (0.1 mL, 0.81 mmol), stirred for 15 minutes under a nitrogenatmosphere, warmed to room temperature for 1 h, and quenched withsaturated sodium bicarbonate. The reaction mixture was partitionedbetween methylene chloride and H₂O; and the aqueous phase was extractedwith methylene chloride. The organic phase and the extracts werecombined, washed with brine, dried over MgSO₄ and concentrated in vacuoto give 1-fluoro-4-iodo-2-pent-4-en-1-ylbenzene as a clear oil, 0.18 g(76% yield).

Step b)2-amino-5-[4-(difluoromethoxy)phenyl]-5-(4-flroro-3-pent-4-en-1-yl)-3-methyl-3,5-dihydro-4H-imidazol-4-one

Using essentially the same procedure described in Example 60 andemploying 1-fluoro-4-iodo-2-pent-4-en-1-ylbenzene as starting material,the title compound was obtained as a slight yellow foam, mp 45-46° C.,identified by NMR and mass spectral analyses. MS (ES−): 416 (M−H)

EXAMPLE 84 Preparation of2-Amino-5-(3-but-3-en-1-yl-4fluorophenyl)-5-[4-(difluoromethoxy)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one

Using essentially the same procedure described in Example 83 andemploying allyl magnesioum bromide in Step a, the title product wasobtained as a slight yellow foam, mp 55-58° C., identified by NMR andmass spectral analyses. MS (ES+): 404 (M+H).

EXAMPLE 85 Preparation of2-Amino-5-[4-(difluoromethoxy)phenyl]-5-[3-(1-hydroxybut-2-yn-1-yl)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one

A stirred solution of3-[2-(4-difluoromethoxyphenyl)-2-oxo-acetyl]-benzaldehyde (0.1 g, 0.33mmol) in dry DME at 0° C. under nitrogen was treated over 10 min with0.5 M 1-propynyl magnesium bromide in THF. The reaction was stirred for0.5 h, quenched with saturated ammonium chloride, diluted with water andextracted with ethyl acetate. The combined extracts were dried overMgSO₄ and concentrated in vacuo. Purification of the resultant residueby flash chromatography (20% to 40% ethyl acetate/petroleum ether) gave1-(4-difluoromethoxyphenyl)-2-[3-(1-hydroxybut-2-ynyl)phenyl]ethane-1,2-dioneas a clear oil, 55 mg (49% yield). Using essentially the same proceduredescribed as described in Example 1, step c, and employing1-(4-difluoromethoxyphenyl)-2-[3-(1-hydroxy-but-2-ynyl)phenyl]-ethane-1,2-dione(0.055 g, 0.16 mmol), the title product was obtained as a slight yellowfoam, 0.044 g (69% yield), identified by NMR and mass spectral analyses.MS (ES+): 400 (M+H).

EXAMPLE 86 Preparation of2-Amino-5-[4-(difluoromethoxy)phenyl]-5-[3-(1,4-dihydroxybut-2-yn-1-yl)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one

A stirred solution of propargyl alcohol (0.1 g, 1.78 mmol) in dry THF at−78° C. under nitrogen was treated dropwise with 1.9 M n-BuLi (1.88 mL,3.57 mmol) over 10 min, stirred for 0.5 h and warmed to 0° C. A 3 mLportion of this solution was added to a stirred solution of3-[2-(4-difluoromethoxyphenyl)-2-oxo-acetyl]benzaldehyde (0.15 g, 0.49mmol) in dry DME at 0° C. under nitrogen. After 10 min, the reactionmixture was quenched with saturated ammonium chloride, diluted withwater and extracted with ethyl acetate. The combined extracts were driedover MgSO₄ and concentrated in vacuo. Purification of the resultantresidue by flash chromatography (30% to 70% ethyl acetate/petroleumether) gave1-[4-(difluoromethoxy)phenyl]-2-[3-(1,4-dihydroxybut-2-ynyl)phenyl]ethane-1,2-dioneas a clear oil, 52 mg (29% yield). Using essentially the same proceduredescribed in Example 1, step c, and employing1-[4-(difluoromethoxy)phenyl]-2-[3-(1,4-dihydroxybut-2-ynyl)phenyl]ethane-1,2-dione(0.052 g, 0.14 mmol), the title compound was obtained as a slight brownfoam, 0.031 g (52% yield), identified by NMR and mass spectral analyses.MS (ES+): 416 (M+H).

EXAMPLE 87 Preparation of2-Amino-5-[4-(difluoromethoxy)phenyl]-5-[3-(2,2-dimethyl-3-oxocyclobutyl)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one

Step a) 3-(3-Bromo-phenyl)-2,2-dimethyl-cyclobutanone

A solution of N,N,2-trimethylpropionamide (3.65 g, 31.7 mmol) anddichloromethane under nitrogen at −13° C., was treated via syringe withtriflic anhydride (Tf₂O), stirred for 10 minutes, treated dropwise over40 minutes with a solution of 3-bromostyrene (5.04 g, 27.6 mmol) and2,4,6-collidine (4.32 g, 35.7 mmol) in CH₂Cl₂, heated at refluxtemperature for 20 h, cooled to room temperature and concentrated invacuo. The concentrate was diluted with water and CH₂Cl₂ and heated at89° C. for 7 h. After cooling to room temperature, the phases wereseparated; and the aqueous phase was extracted with CH₂Cl₂ The organicphase and the extracts were combined, dried over Na₂SO₄ and concentratedin vacuo. Purification of the resultant concentrate by silica gel columnchromatography (gradient; 5%-10% EtOAc in hexanes) afforded3-(3-bromophenyl)-2,2-dimethyl-cyclobutanone as a pale yellow oil, 4.26g (61% yield); 1H NMR (400 MHz, DMSO-d₆) δ ppm 0.69 (s, 3 H) 1.25 (s, 3H) 3.24 (dd, J=17.4, 9.0 Hz, 1 H) 3.44 (t, J=8.9 Hz, 1 H) 3.64 (dd,J=17.3, 8.7 Hz, 1 H) 7.23-7.35 (m, 2 H) 7.43-7.47 (m, 1 H) 7.49 (s, 1H);

Step b)2-amino-5-[4-(difluoromethoxy)phenyl]-5-[3-(2,2-dimethyl-3-oxocyclobutyl)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one

Using essentially the same procedure described in Example 17, step d,and employing 3-(3-bromophenyl)-2,2-dimethyl-cyclobutanone as startingmaterial, the title compound was obtained as a white solid, mp 172-174°C.; ¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.61 (s, 3 H) 1.21 (s, 3 H) 2.98 (s,3 H) 3.19-3.28 (m, 1 H) 3.34-3.40 (m, 1 H) 3.41-3.47 (m, J=4.9 Hz, 1 H)6.71 (s, 2 H) 6.96-7.19 (m, 4 H) 7.24-7.37 (m, 3 H) 7.44 (d, J=7.9 Hz, 2H); MS (ES) m/z 426.2 [M−H]−; HRMS: calcd for C₂₃H₂₃F₂N₃O₃+H+,428.17802. found (ESI, [M+H]+), 428.1780.

EXAMPLE 88 Preparation of2-Amino-5-[4-(difluoromethoxy)phenyl]-3-methyl-5-[3-(3-oxocyclobutyl)phenyl]-3,5-dihydro-4H-imidazol-4-one

Using essentially the same procedure described in Example 87 andemploying N,N-dimethylacetamide in Step a, the title product wasobtained a white solid, mp 68-70° C. (foams); ¹H NMR (400 MHz, DMSO-d₆)δ ppm 2.97 (s, 3 H) 3.06-3.17 (m, 2 H) 3.36-3.46 (m, 2 H) 3.59 (q, J=7.3Hz, 1 H) 6.68 (s, 2 H) 7.10 (d, J=8.8 Hz, 2 H) 7.16 (t, J=74.2 Hz, 1 H)7.23-7.34 (m, 3 H) 7.39-7.50 (m, 3 H); MS (ES) m/z 398.1 [M−H]−; HRMS:calcd for C₂₁H₁₉F₂N₃O₃+H+, 400.14672. found (ESI, [M+H]+), 400.1475.

EXAMPLE 89 Preparation of2-Amino-5-[4-(difluoromethoxy)phenyl]-5-[3-(3-hydroxycyclobutyl)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one

A methanolic solution of2-amino-5-[4-(difluoromethoxy)phenyl]-3-methyl-5-[3-(3-oxocyclobutyl)phenyl]-3,5-dihydro-4H-imidazol-4-one(0.324 gm, 0.811 mmol) at ice bath temperatures was treated all at oncewith NaBH₄ (0.042 gm, 1.11 mmol), stirred at 0° C. for 45 minutes andconcentrated in vacuo. The solid residue was partitioned between waterand chloroform. The organic phase was separated, dried over sodiumsulfate and evaporated to a foam. This foam was dissolved in chloroformand precipitated with hexane to give the title compound as a whitesolid, 0.307 g (94% yield), mp 186-190° C.; ¹H NMR (400 MHz, DMSO-d₆) δppm 1.70-1.86 (m, 2 H) 2.53-2.60 (m, 2 H) 2.70-2.85 (m, 1 H) 2.97 (s, 3H) 3.89-4.08 (m, 1 H) 5.08 (t, J=5.2 Hz, 1 H) 6.69 (s, 2 H) 7.10 (d,J=8.6 Hz, 3 H) 7.17 (t, J=74.2 Hz, 1 H) 7.19-7.33 (m, 3 H) 7.45 (d,J=8.8 Hz, 2 H); MS (ES) m/z 400.2 [M−H]−; HRMS: calcd forC₂₁H₂₁F₂N₃O₃+H+, 402.16237. found (ESI, [M+H]+), 402.1630.

EXAMPLE 90 Preparation of Ethyl[3-(3-{2-Amino-4-[4-(difluoromethoxy)phenyl]-1-methyl-5-oxo-4,5-dihydro-1H-imidazol-4-yl}phenyl)cyclobutylidene]acetate

Step a) [3-(3-bromophenyl)cyclobutylidene]acetic acid ethyl ester

A solution of 3-(3-bromophenyl)cyclobutanone (2.03 g 9.02 mmol) andtriphenylphosphoranylidene acetic acid ethyl ester (15.72 gms 45.12mmol) dichloromethane was irradiated in a CEM Discover™ microwaveinstrument for 30 minutes at 120° C. Pressure reached a maximum of 180PSI. Standard work-up procedures followed by purification by columnchromatography (isocratic; 10% diethyl ether in hexanes) afforded[3-(3-bromophenyl)cyclobutylidene]acetic acid ethyl ester as an oil,2.37 g (89% yield), 1H NMR (400 MHz, DMSO-d₆) δ ppm 1.20 (t, J=7.1 Hz, 3H) 2.89-3.00 (m, 1 H) 3.03-3.11 (m, 1 H) 3.16-3.27 (m, 1 H) 3.46-3.57(m, 1 H) 3.63 (q, J=8.0 Hz, 1 H) 4.08 (q, J=7.0 Hz, 2 H) 5.71 (q, J=2.9Hz, 1 H) 7.25-7.35 (m, 2 H) 7.39-7.43 (m, 1 H) 7.48-7.52 (m, 1 H); MS(APPI) m/z 295 [M+H]+.

Step b) ethyl[3-(3-{2-Amino-4-[4-(difluoromethoxy)phenyl]-1-methyl-5-oxo-4,5-dihydro-1H-imidazol-4-yl}phenyl)-1-methoxycyclobutylidene]acetate

Using essentially the same procedure described in Example 17, step d,and employing [3-(3-bromophenyl)cyclobutylidene]acetic acid ethyl ester,the title compound is obtained as a white foam solid, mp 78-80° C.; ¹HNMR (400 MHz, DMSO-d₆) δ ppm 1.19 (t, J=7.1 Hz, 3 H) 2.78-2.89 (m, 1 H)2.97 (s, 3 H) 3.02-3.07 (m, 1 H) 3.16-3.26 (m, 1 H) 3.45-3.53 (m, 1 H)3.55-3.66 (m, 1 H) 4.07 (q, J=7.0 Hz, 2 H) 5.64-5.75 (m, 1 H) 6.67 (s, 2H) 7.05-7.11 (m, 2 H) 7.16 (t, J=74.2 Hz, 1 H) 7.17-7.21 (m, 1 H)7.23-7.33 (m, 2 H) 7.37 (s, 1 H) 7.43-7.51 (m, 2 H); MS (ES) m/z 468.1[M−H]−.

EXAMPLE 91 Preparation of Methyl[3-(3-{2-Amino-4-[4-(difluoromethoxy)phenyl]-1-methyl-5-oxo-4,5-dihydro-1H-imidazol-4-yl}phenyl)cyclobutylidene]acetate

Using essentially the same procedure described in Example 90 andemploying triphenylphosphoranylidene acetic acid ethyl ester in step a,the title product was obtained as a foam. NMR analysis indicates thefoam is a 7:3 mixture of methyl and ethyl esters. ¹H NMR (400 MHz,DMSO-d₆), a mixture of methyl and ethyl esters (7:3) δ ppm 1.15-1.23 (m,3 H of ethyl ester) 2.76-2.91 (m, 1 H) 2.97 (s, 3 H) 2.99-3.07 (m, 1 H)3.11-3.27 (m, 1 H) 3.42-3.55 (m, 1 H) 3.55-3.60 (m, 1 H) 3.61 (s, 3 H ofmethyl ester) 4.01-4.12 (m, 2 H of ethyl ester) 5.64-5.77 (m, 1 H) 6.68(s, 2 H) 7.10 (d, J=8.8 Hz, 2 H) 7.16 (t, J=74.2 Hz, 1 H) 7.18-7.22 (m,1 H) 7.23-7.33 (m, 2 H) 7.35-7.38 (m, 1 H) 7.46 (dt, J=9.2, 2.6 Hz, 2H). MS (ES) m/z 454.1 (Me ester) [M−H]−; MS (ES) m/z 468.1 (Et ester)[M−H]−

EXAMPLE 92 Preparation of Methyl[3-(3-{2-Amino-4-[4-(difluoromethoxy)phenyl]-1-methyl-5-oxo-4,5-dihydro-1H-imidazol-4-ylphenyl)cyclobutyl]acetate

Step a)(3-{3-[2-(4-Difluoromethoxyphenyl)-1,2-dihydroxyethyl]phenyl}-cyclobutyl)aceticacid methyl ester

A mixture of 10% Pd/C (0.092 g) and(3-{3-[2-(4-difluoromethoxyphenyl)-2-oxoacetyl]-henyl}-cyclobutylidene)aceticacid methyl ester (0.78 g, 1.95 mmol) in ethanol was placed on a ParrHydrogenator under 15 PSI hydrogen for 3 hours. More 10% Pd/C (0.056 g)was added and the shaker was placed under 30 PSI hydrogen atmosphere for2 hours. The reaction mixture was filtered thru Celite. The filtrate wasconcentrated in vacuo to give(3-{3-[2-(4-Difluoromethoxyphenyl)-1,2-dihydroxyethyl]phenyl}-cyclobutyl)aceticacid methyl ester as an oil, 402 mg (51% yield); 1H NMR (400 MHz,DMSO-d₆) δ ppm 1.67 (q, J=9.1 Hz, 1 H) 1.92-2.07 (m, 1 H) 2.13-2.23 (m,1 H) 2.32-2.44 (m, 3 H) 2.56-2.64 (m, 1 H) 3.35-3.44 (m, 1 H) 3.55-3.65(m, 3 H) 4.45-4.63 (m, 2 H) 5.08-5.38 (m, 2 H) 6.56-7.43 (m, 9 H); MS(ES) m/z 405.1 [M−H]−

Step b)1-(4-difluoromethoxyphenyl)-2-[3-(3-oxocyclobutyl)-phenyl]ethane-1,2-dione

A mixture of a 1M solution of o-iodoxybenzoic acid (IBX) in DMSO (0.90mL) and(3-{3-[2-(4-difluoromethoxyphenyl)-1,2-dihydroxyethyl]phenyl-cyclobutyl)aceticacid methyl ester (0.144 g, 0.354 mmol) was stirred for 30 min, treatedwith an additional 1.2 mL of 1M IBX in DMSO, stirred for 15 min andpartitioned between water and diethyl ether. The organic phase isseparated, dried over Na₂SO₄ and concentrated in vacuo. Purification ofthe resultant residue by column chromatography (10% hexane in ethylacetate) afforded1-(4-difluoromethoxyphenyl)-2-[3-(3-oxocyclobutyl)phenyl]ethane-1,2-dioneas an oil, 0.133 g (93% yield); ¹H NMR (400 MHz, DMSO-d₆) δ ppm1.71-1.87 (m, 2 H) 2.06-2.17 (m, 1 H) 2.26 (s, 1 H) 2.55-2.69 (m, 2 H)3.46 (s, 1 H) 3.54-3.62 (m, 3 H) 3.73 (s, 1 H) 7.23-7.82 (m, 7 H)7.95-8.06 (m, 2 H); MS (ES) m/z 403.0 [M+H]+

Step c) methyl[3-(3-{2-amino-4-[4-(difluoromethoxy)phenyl]-1-methyl-5-oxo-4,5-dihydro-1H-imidazol-4-yl}phenyl)cyclobutyl]acetate

Using essentially the same procedure described in Example 1, step c, andemploying1-(4-difluoromethoxyphenyl)-2-[3-(3-oxocyclobutyl)phenyl]ethane-1,2-dioneas starting material, the title compound was obtained as a white solid,mp 68-70° C. (foams); ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.63-1.76 (m, 2 H)1.98-2.04 (m, 1 H) 2.11-2.18 (m, 1 H) 2.36-2.46 (m, 4 H) 2.58-2.65 (m, 2H) 3.02 (s, 3 H) 3.54-3.62 (m, 3 H) 7.10-7.17 (m, J=7.6, 7.6 Hz, 3 H)7.19 (t, J=74.1 Hz, 1 H) 7.21-7.31 (m, 3 H) 7.41-7.47 (m, 2 H); MS (ES)m/z 456.1 [M−H]−

EXAMPLE 93 Preparation of2-Amino-5-[3-(difluoromethoxy)phenyl]-5-[4-(difluoromethoxy)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one

Using essentially the same procedure described in Example 18, step d,and employing 4-difluoromethoxybromobenzene and1-difluoromethoxy-3-ethynylbenzene as starting material, the titlecompound was obtained as a white foam, mp 52-54° C.; 1H NMR (400 MHz,DMSO-d₆) δ ppm 2.98 (s, 3 H) 6.75 (s, 2 H) 6.96-7.13 (m, 3 H) 7.17 (d,J=2.9 Hz, 1 H) 7.24 (s, 1 H) 7.33-7.38 (m, 3 H) 7.48 (d, J=8.8 Hz, 2 H);MS (ES) m/z 398.1 [M+H]+.

EXAMPLE 94 Preparation of(5S)-2-Amino-5-[3-(difluoromethoxy)phenyl]-5-[4-(difluoromethoxy)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one(A) and(5R)-2-Amino-5-[3-(difluoromethoxy)phenyl]-5-[4-(difluoromethoxy)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one(B)

A racemic mixture of2-amino-5-[3-(difluoromethoxy)phenyl]-5-[4-(difluoromethoxy)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-onewas placed on a Chiralcel OJ, 2×25 cm column (elution 10% EtOH inHexane/DEA at a flow rate of 22 mL/min). Material was collected at 6.14minutes (product A) and at 7.42 minutes (product B). Separately eachenantiomer product was concentrated at the rotovap, diluted with ethanoland concentrated again to give an oily residue. Each oily residue wasdiluted with diethyl ether and an equal volume of hexane andconcentrated to give the title enantiomeric products as a white solid: A(118 mg) and B (96 mg). Product A was identified as the (+)-enantiomer,[α]_(D) ²⁵=8.6° (c=1% MeOH); 1H NMR (400 MHz, DMSO-d₆) α ppm 2.98 (s, 3H) 6.75 (s, 2 H) 6.96-7.13 (m, 3 H) 7.17 (d, J=2.9 Hz, 1 H) 7.24 (s, 1H) 7.33-7.38 (m, 3 H) 7.48 (d, J=8.8 Hz, 2 H); MS (ES) m/z 396.1 [M−H]−;and Product B was identified as the (R)-enantiomer, [α]_(D) ²⁵=−8.2°(c=1% MeOH); 1H NMR (400 MHz, DMSO-d₆) δ ppm 2.98 (s, 3 H) 6.75 (s, 2 H)6.96-7.13 (m, 3 H) 7.17 (d, J=2.9 Hz, 1 H) 7.24 (s, 1 H) 7.33-7.38 (m, 3H) 7.48 (d, J=8.8 Hz, 2 H); MS (ES) m/z 398.1 [M+H]+.;

EXAMPLE 95 Preparation of2-Amino-5-[4-(difluoromethoxy)phenyl]-5-{3-[(1R)-1-fluoropent-4-en-1-yl]pheny}-3-methyl-3,5-dihydro-4H-imidazol-4-one

Step a) (3-Bromophenyl)acetaldehyde

A mixture of lead tetraacetate (3.6 g, 8.2 mmol) and trifluoroaceticacid (8.25 mL) at 0° C. is treated dropwise with a solution of1-bromo-3-vinylbenzene (1.5 g, 8.2 ml) in dichloromethane, allowed towarm to room temperature, stirred for 2 h at room temperature, dilutedwith dichloromethane, poured into water, stirred vigorously and filteredthrough a pad of celite. The filtrate is separated. The filtercake isrinsed with additional portions of dichloromethane. The combined organicphases are washed sequentially with water, NaHCO₃ and brine, dried overMgSO₄ and concentrated in vacuo to afford (3-bromophenyl)acetaldehyde.

Step b) (R)-2-Fluro-2-(3-bromophenyl)acetaldehyde

(Lit. Ref: MacMillan and Beeson, JACS 2005, 127, 8826)

A homogeneous mixture of (5R)-5-benzyl-2,2,3-trimethylimidazolidin-4-one dichloroaccetic acid salt (97 mg, 0.4 mmol) andN-fluorobenzenesulfonimide (3.15 g, 10 mmol) in a 9:1 mixture of acetoneand isopropanol at room temperature is treated with(3-bromophenyl)acetaldehyde (280 mg, 1.4 mmol), stirred for 1 h at roomtemperature, cooled to −78° C., diluted with ether, and filtered througha pad of celite. The filtercake is washed with additional ether. Thecombined filtrates are treated with methylsulfide (5 mL), washed withsaturated NaHCO₃ and brine, dried over MgSO₄ and concentrated underreduced pressure to give (R)-2-fluro-2-(3-bromophenyl)acetaldehyde.

Step c) Toluene-4-sulfonic acid (S)-2-(3-bromophenyl)-2-fluoro-ethylester

A solution of (R)-2-fluoro-2-(3-bromophenyl)acetaldehyde in CH₂Cl₂ andethanol is treated with NaBH₄ (189 mg, 5 mmol), stirred for 30 min,cooled to 0° C., treated with saturated NH₄Cl, warmed to roomtemperature, stirred vigorously for 1 h at room temperature and dilutedwith CH₂Cl₂. The phases are separated. The aqueous phase is extractedwith CH₂Cl₂. The organic phase and the extracts are combined, washedwith NaHCO₃ and brine, dried over MgSO₄ and concentrated in vacuo. Theresultant residue is purified by column chromatography (5% EtOAc andhexane as eluant)to give (R)-2-fluro-2-(3-bromophenyl)-1-ethanol.

A solution of (R)-2-fluro-2-(3-bromophenyl)-1-ethanol (5 mmol) andp-toluenesulfonyl chloride (5.1 mmol) in CH₂Cl₂ at ice bath temperaturesis treated with stirring with pyridine. The reaction mixture is heatedat reflux temperature under a nitrogen atmosphere for 16 h, cooled toroom temperature, washed with 10% HCl, saturated NaHCO₃ and brine, driedover MgSO₄ and concentrated in vacuo to give toluene4-sulfonic acid(S)-2-(3-bromophenyl)-2-fluoro-ethyl ester.

Step d) 1-Bromo-(S)-3-(1-fluoropent-4-en-1-yl)benzene

A solution of toluene-4-sulfonic acid(S)-2-(3-bromophenyl)-2-fluoro-ethyl ester (5 mmol) in THF at roomtemperature is treated dropwise with a 1M solution of allylmagnesiumbromide, stirred at room temperature for 5 h, quenched with saturatedNH₄Cl and extracted with ethyl acetate. The extracts are combined,washed sequentially with water and brine, dried over MgSO₄ andconcentrated in vacuo to afford1-bromo-(S)-3-(1-fluoropent-4-en-1-yl)benzene.

Step e)2-Amino-5-[4-(difluoromethoxy)phenyl]-5-{3-[(1R)-1-fluoropent-4-en-1-yl]phenyl}-3-methyl-3,5-dihydro-4H-imidazol-4-one

Using essentially the same procedure described in Example 14, steps f, gand h, and employing 1-bromo-(S)-3-(1-fluoropent-4-en-1-yl)benzene asthe starting material, the title product is obtained and identified byNMR and mass spectral analyses.

EXAMPLE 96 Preparation of2-Amino-5-[4-(difluoromethoxy)phenyl]-5-{3-[(1R)-1-fluorobut-3-en-1-yl]phenyl}-3-methyl-3,5-dihydro-4H-imidazol-4-one

Using essentially the same procedure described in Example 95 andemploying ethenylmagnesium bromide in step d, the title compound isobtained and identified by NMR and mass spectral analyses.

EXAMPLE 97 Preparation ofN-(3-{2-Amino-4-[4-(difluoromethoxy)phenyl]-1-methyl-5-oxo-4,5-dihydro-1H-imidazol-4-yl}phenyl)ethanesulfonamide

Step a)N-(3-{[4-(difluoromethoxy)phenyl]ethynyl}phenyl)ethanesulfonamide

A cold (0° C.) solution of 3-{[4-(difluoromethoxy)phenyl]ethynyl}aniline(0.5 g, 1.93 mmol) and pyridine (0.31 mL, 3.80 mmol) in CH₂Cl₂ wastreated dropwise with ethylsulfonyl chloride (0.27 mL, 2.89 mmol). Themixture was stirred for 5 hours, poured into water and extracted withEtOAc/ethyl ether 1/1. The organic extracts were combined, dried overMgSO₄ and concentrated in vacuo. Purification of the resultant residueon silica gel (Biotage) using hexanes/EtOAc (3/1) as the eluting solventgave N-(3-{[4-(difluoromethoxy)phenyl]ethynyl}phenyl)ethanesulfonamideas a yellow oil (0.62 g).

Step b)N-(3-{2-amino-4-[4-(difluoromethoxy)phenyl]-1-methyl-5-oxo-4,5-dihydro-1H-imidazol-4-yl}phenyl)ethanesulfonamide

Using essentially the same procedure described in Example 12, steps cand d, and employingN-(3-{[4-(difluoromethoxy)phenyl]ethynyl}phenyl)ethanesulfonamide asstarting material, the title compound was obtained as a white solid,identified by NMR and mass spectral analyses. [M+H]⁺ 439.1

EXAMPLES 98-108 Preparation ofN-(3-{2-Amino-4-[4-(difluoromethoxy)phenyl]-1-methyl-5-oxo-4,5-dihydro-1H-imidazol-4-yl}phenyl)sulfonamideCompounds

Using essentially the same procedure described in Example 97 andemploying the desired sulfonyl chloride in step a, the compounds shownon Table V were obtained and identified by NMR and mass spectralanalyses.

TABLE V

Ex. m/e No. R [M + H]⁺ 98 3,4-difluorophenyl 523 99 3-methoxyphenyl517.1 100 3-chlorophenyl 521 101 n-propyl 453.1 102 3-cyanophenyl 512.1103 3-(trifluoromethoxy)phenyl 571.1 104 3-pyridyl 488.1 1054-cyanophenyl 512.1 106 2-thienyl 493 107 benzyl 501.1 1083,5-difluorophenyl 523.1

EXAMPLES 109-112 Preparation ofN-(3-{2-Amino-4-[4-(difluoromethoxy)phenyl]-1-methyl-5-oxo-4,5-dihydro-1H-imidazol-4-yl}phenyl)acetamideCompounds

Using essentially the same procedure described in Example 97 andemploying the appropriate acid chloride in step a, the compounds shownon Table VI were obtained and identified by NMR and mass spectralanalyses. Chiral separation was achieved using essentially the sameprocedure described in Example 1, step d.

TABLE VI

Ex. No. Chiral R R′ [M + H] [α]_(D) ²⁵* 109 — CH₂OCH₃ H 419.1 110 —CH₂OCH₃ CH₃ 433.1 111 4-R CH₂OCH₃ H 419.2 +19.2 112 4-S CH₂OCH₃ H417.3** −15.2 *1% Methanol Solution **[M − H]⁻

EXAMPLE 113 Preparation of2-Amino-5-[4-(difluoromethoxy)phenyl]-5-[3-(5-hydroxypent-1-yn-1-yl)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one

A mixture of2-amino-5-(3-bromophenyl)-5-[4-(difluoromethoxy)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one(1.15 g, 2.8 mmol), dioxane, bis(benzonitrile)dichloropalladium(II)(32.2 mg, 0.084 mmol), tri-tert-butyl phosphine (10% w/w in hexane, 339mg, 0.17 mmol) and diisopropyl amine (340 mg, 3.36 mmol) was degassedunder argon for 5 minutes, treated with pent-4-yn-1-ol (236 mg, 2.8mmol), stirred at 80° C. for 5 hours, poured into water and extractedwith ethyl acetate. The organic extracts were combined, dried over MgSO₄and concentrated in vacuo. Purification of the resultant residue by ICSO(EtOAc/MeOH 10/1) gave the title compound as a white solid (849 mg),identified by NMR and mass spectral analyses. MS m/e [M+H]⁺ 414.2

EXAMPLES 114-173 Preparation of2-Amino-5-[4-(difluoromethoxy)phenyl]-5-(3-alkynylphenyl)-3-methyl-3,5-dihydro-4H-imidazol-4-oneCompounds

Using essentially the same procedure described in Example 113 andemploying the desired alkyne reagent, the compounds shown on Table VIIwere obtained and identified by NMR and mass spectral analyses. Chiralseparation was achieved using essentially the same procedure describedin Example 1, step d.

TABLE VII

Ex. m/e No. Chiral R R5 [M + H] [a]_(D) ²⁵* 114 — CH₂CH₂CH₂F H 416.1 115— CH₂CH₂CH₂Cl H 432   116 — CH₂CH₂CH₃ H 398.1 117 — CH₂CH₂OH H 400.2 118— CH₂CH₂CH₂CH₂OH H 428.2 119 — CH₂CH₂CH₂CH₂F H 430.2 120 — CH₂CH₂Cl H418   121 5-R CH₂CH₃ H 398   +12.8 122 5-S CH₂CH₃ H 398    −9.8 123 5-SCH₂CH₂CH₂OH H 414.1 +12.4 124 5-R CH₂CH₂CH₂CH₂OH H 428   +10.2 125 5-SCH₂CH₂CH₂CH₂OH H 428   −11.4 126 5-R CH₂CH₂OH H 400   127 5-S CH₂CH₂OH H400   −13   128 5-S CH₂CH₂CH₂F H 416.1 −11.4 129 5-R CH₂CH₂CH₂F H 416.1+19   130 5-S CH₂CH₂CH₂OH F 432.1 +11.6 131 5-R CH₂CH₂CH₂OH F 432.1 1325-S CH₂CH₂CH₂F F 432.1  +8.6 133 5-R CH₂CH₂CH₂F F 434.2  −8.4 134 —CH₂CH₂OCH₃ H 414.1 135 — CH₂OCH₃ H 400.1 136 5-S CH₂CH₂OCH₃ H 414.2−12   137 5-R CH₂CH₂OCH₃ H 414.2 +10.6 138 — CH₂CH₂F H 402.2 139 —CH₂CH(CH₃)₂ H 412.2 140 — CH(OH)CH₂CH₃ H 414.1 141 — CH₂CH(OH)CH₃ H414.2 142 — CH(CH₃)₂ H 398.1 143 — CH₂CH₃ H 384.2 144 — CH₂CH₂CH₂CH₃ H412.2 145 — cyclopropyl H 396.2 146 — cyclohexyl H 438.2 147 —cyclopentylmethyl H 438.2 148 — cyclohexylmethyl H 452.2 149 5-S CH₂OCH₃H 400    −6.8 150 5-R CH₂OCH₃ H 400   151 — CH₂OCH₃ F 418   152 —CH₂CH₂OCH₃ F 432   153 — CH₂OH H 386.1 154 — (S)-CH(OH)CH₃ H 400.1 155 —(R)-CH(OH)CH₃ H 400.1 156 — CH(OH)CH(CH₃)₂ H 428.2 157 —1-hydroxycyclopentyl H 440.2 158 — 1-hydroxycyclohexyl H 454.2 159 —C(OH)(CH₃)₂ H 414.2 160 — C(OH)(CH₃)CH₂CH₃ H 428.2 161 — H H 356.1 162 —(S)-CH(OH)C₆H₅ H 462.1 163 5-S CH₂CH₂OCH₃ H 432    +7.8 164 5-RCH₂CH₂OCH₃ H 432.1  −6.6 165 5-S CH₂OCH₃ H 418.1 166 5-R CH₂OCH₃ H 418.1167 — CH₃ F 388.1 168 — CH₃ H 370.1 169 5-R (S)-CH(OH)CH₃ H 400.1 −19.2170 5-S (S)-CH(OH)CH₃ H 400.1 171 5-R CH₃ H 370.1 −15.6 172 5-S CH₃ H370.1 +15   173 5-R CH₂CH₂CH₂OH H 414.1 *1% Methanol Solution **[M − H]⁻

EXAMPLE 174 Preparation of2-Amino-5-{3-[(E)-2-cyclopropylvinyl]phenyl}-5-[4-(difluoromethoxy)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one

A mixture of2-amino-5-(3-bromophenyl)-5-[4-(difluoromethoxy)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one(150 g, 0.36 mmol), dimethoxyethane,2-[(E)-2-cyclopropylvinyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (105mg) and Na₂CO₃ (2 M, 2.5 mL) was degassed under argon for 5 minutes andtreated with tetrakis(triphenylphosphine)palladium(0) (21 mg, 0.018mmol). The reaction mixture was stirred for 15 hour, poured into waterand extracted with ethyl acetate. The extracts were combined, dried overMgSO₄ and concentrated in vacuo. Purification of the resultant residueby ICSO (EtOAc/MeOH 10/1) gave the title product as a white solid (98mg), identified by NMR and mass spectral analyses.

EXAMPLES 175-187 Preparation of2-Amino-5-[3-(2-substituted-vinyl)phenyl]-5-[4-(difluoromethoxy)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-oneCompounds

Using essentially the same procedure described in Example 174 andemploying either the vinyldiborolane reagent or the vinyl tributyltinreagent, the compounds shown in Table VIII are obtained and identifiedby NMR and mass spectral analyses.

TABLE VIII

Ex. m/e No. R R′ R″ R5 [M + H] 175 CH₃ H H H 372.1 176 CH₃ H H F 390.1177 H H H H 358.1 178 CH₃ CH₃ H F 418   179 H H CH₃ H 372.1 180CH₂CH₂CH₃ H H H 400.2 181 CH₂CH₂CH₂CH₂CH₃ H H H 428.2 182 CH₂CH₂CH_(2Cl)H H H 434.1 183 C₆H₅ H H H 434.2 184 2,4-difluorophenyl H H H 470.1 185CH₂CH₂CH₂CH₂CH₂CH₃ H H H 442.2 186 H H C₆H₅ H 434.1 187 CH₂CH₂CH₂CH₃ H HH 414.2

EXAMPLE 188 Evaluation of BACE1 Binding Affinity of Test Compounds

Fluorescent Kinetic Assays

Final Assay Conditions: 10 nM human BACE1 (or 10 nM Murine BACE1, 1.5 nMhuman BACE2), 25 μM substrate (WABC-6, MW 1549.6, from AnaSpec), Buffer:50 mM Na-Acetate, pH 4.5, 0.05% CHAPS, 25% PBS, room temperature.Na-Acetate was from Aldrich, Cat.# 24, 124-5, CHAPS was from ResearchOrganics, Cat. # 1304C 1×, PBS was from Mediatech (Celigro), Cat#21-031-CV, peptide substrate AbzSEVNLDAEFRDpa was from AnaSpec, PeptideName: WABC-6Determination of stock substrate (AbzSEVNLDAEFRDpa) concentration: ˜25mM stock solution is made in DMSO using the peptide weight and MW, anddiluted to ˜25 μM (1:1000) in 1×PBS. Concentration is determined byabsorbance at 354 nm using an extinction coefficient ε of 18172 M⁻¹cm⁻¹, the concentration of stock substrate is corrected, and thesubstrate stock stored in small aliquots in −80° C.[Substrate Stock]=ABS^(354 nm)*10⁶/18172 (in mM)The extinction coefficient ε^(354 nm) was adapted from TACE peptidesubstrate, which had the same quencher-fluorophore pair.Determination of Stock Enzyme Concentration: the stock concentration ofeach enzyme is determined by absorbance at 280 nm using an ε of 64150M⁻¹ cm⁻¹ for hBACE1 and MuBACE1, 62870 M⁻¹ cm⁻¹ for hBACE2 in 6 MGuanidinium Hydrochloride (from Research Organics, Cat. # 5134G-2), pH˜6. The extinction coefficient ε^(280 nm) for each enzyme was calculatedbased on known amino acid composition and published extinctioncoefficients for Trp (5.69 M⁻¹ cm⁻¹) and Tyr (1.28 M⁻¹ cm⁻¹) residues(Anal. Biochem. 182, 319-326).Dilution and mixing steps: total reaction volume: 100 μL

2× inhibitor dilutions in buffer A (66.7 mM Na-Acetate, pH 4.5, 0.0667%CHAPS) were prepared,

4× enzyme dilution in buffer A (66.7 mM Na-Acetate, pH 4.5, 0.0667%CHAPS) were prepared,

100 μM substrate dilution in 1×PBS was prepared, and

50 μL 2× Inhibitor, 25 μL 100 μM substrate are added to each well of96-well plate (from DYNEX Technologies, VWR #: 11311-046), immediatelyfollowed by 25 μL 4× enzyme (added to the inhibitor and substrate mix),and the fluorescence readings are initiated.

Fluorescence Readings: Readings at λ_(ex) 320 nm and λ_(em) 420 nm aretaken every 40 sec for 30 min at room temperature and the linear slopefor substrate cleavage rate (v_(i)) determined.

Calculation of % Inhibition:% Inhibition=100*(1−v _(i) /v ₀)v_(i): substrate cleavage rate in the presence of inhibitorv₀: substrate cleavage rate in the absence of inhibitorIC₅₀ Determination:% Inhibition=((B*IC ₅₀ ^(n))+(100*I ₀ ^(n)))/(IC ₅₀ ^(n) +I ₀ ^(n))(Model # 39 from LSW Tool Bar in Excel where B is the % inhibition fromthe enzyme control, which should be close to 0.) % Inhibition is plottedvs. Inhibitor Concentration (I₀) and the data fit to the above equationto obtain IC₅₀ value and Hill number (n) for each compound. Testing atleast 10 different inhibitor concentrations is preferred.

Results are shown in Table IX.

For Table IX

TABLE IX Example BACE1 No. IC₅₀ μM  1A B  1B C  2 B  3 B  4A A  4B C  5AA  5B C  6 A  7 B  8 A  9 B  10 B  11A A  11B B  12A A  12B B  13 A  14A  15 A  16 A  17 A  18 B  19 A  20 A  21 A  22 B  23 B  24 B  25 A  26B  27 A  28 A  29 B  30 A  31 B  32 B  33 A  34 B  35 B  36 B  37 A  38A  39 B  40 A  41 A  42 A  43 A  44 A  45 A  46 A  47 A  48 A  49 A  50B  51 B  52 C  53 A  54 A  55 C  56 B  57 A  58 B  59 A  60 —  61 A  62B  63 A  64 A  65 B  66 A  67 A  68 B  69 B  70 A  79A A  81 A  97 B  98B  99 B 100 B 101 B 102 B 103 CB 104 B 105 B 106 B 107 B 108 C 109 A 110B 111 A 112 B 113 A 114 A 115 A 116 A 118 — 119 — 120 A 121 A 122 C 123B 124 A 125 — 126 A 127 C 128 C 129 A 130 C 131 A 132 B 133 A 134 A 135A 136 C 137 A 138 A 139 A 140 A 141 A 142 A 143 A 144 A 145 A 146 B 147B 148 C 149 B 150 A 151 A 152 A 153 A 154 A 155 A 156 B 157 B 158 B 159A 160 B 161 B 162 B 163 C 164 A 165 C 166 A 167 B 168 A 169 — 170 A 171— 172 A 173 174 A 175 B 176 B 177 B 178 B 179 C 180 B 181 C 182 A 183 B184 B 185 C 186 C 187 B

1. A compound of formula I

wherein R₁ and R₂ are each independently H or an alkyl, cycloalkyl,cycloheteroalkyl, aryl or heteroaryl group each optionally substitutedor R₁ and R₂ may be taken together with the atom to which they areattached to form an optionally substituted 5- to 7-membered ringoptionally interrupted by an additional heteroatom selected from O, N orS; R₃ is H or an alkyl, cycloalkyl, cycloheteroalkyl, aryl or heteroarylgroup each optionally substituted; R₄, R₅ and R₆ are each independentlyH, Cl, I, F, NO₂, CN, COR₇, NR₁₀CO₂R₁₁, NR₁₅COR₁₆, OR₁₄, NR₁₂R₁₃,SO_(n)R₁₇ or an alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl,cycloalkyl or cycloheteroalkyl group each optionally substituted or whenattached to adjacent carbon atoms R₄ and R₅ may be taken together withthe atoms to which they are attached to form an optionally substituted5- to 7-membered ring optionally containing one or two heteroatomsselected from O, N or S; n is 0, 1 or 2; R₇ and R₁₇ are eachindependently H, NR₈R₉ or an alkyl, haloalkyl, alkoxyalkyl, alkenyl,alkynyl, cycloalkyl or aryl group each optionally substituted; R₈ and R₉are each independently H or an alkyl, alkenyl, alkynyl or cycloalkylgroup each optionally substituted or R₈ and R₉ may be taken togetherwith the atom to which they are attached to form an optionallysubstituted 5- to 7-membered ring optionally containing an additionalheteroatom selected from O, N or S; R₁₁, R₁₄ and R₁₆ are eachindependently H or an alkyl, haloalkyl, alkoxyalkyl, alkenyl, alkynyl,cycloalkyl or aryl group each optionally substituted; R₁₀ and R₁₅ areeach independently H or an optionally substituted alkyl group; and R₁₂and R₁₃ are each independently H or an alkyl or cycloalkyl group eachoptionally substituted or R₁₂ and R₁₃ may be taken together with theatom to which they are attached to form an optionally substituted 5- to7-membered ring optionally containing an additional heteroatom selectedfrom O, N or S; or a tautomer thereof, a stereoisomer thereof or apharmaceutically acceptable salt thereof.
 2. The compound according toclaim 1 wherein R₁ and R₂ are H.
 3. The compound according to claim 1wherein R₃ is C₁-C₄alkyl.
 4. The compound according to claim 1 whereinR₄, R₅ and R₆ are each independently H, Cl, I, F, COR₇, OR₁₄, or analkyl, haloalkyl, alkoxy, haloalkoxy, alkynyl or cycloalkyl group eachoptionally substituted.
 5. The compound according to claim 2 wherein R₃is methyl.
 6. The compound according to claim 4 wherein R₅ and R₆ areeach independently H, Cl, I, or F.
 7. The compound according to claim 5wherein R₄ is H, COR₇, OR₁₄ or an alkyl, haloalkyl, alkoxy, haloalkoxy,alkynyl or cycloalkyl group each optionally substituted; and R₄ is atthe 3-position of the phenyl ring.
 8. The compound according to claim 7wherein R₅ and R₆ are each independently H, Cl, I, or F.
 9. The compoundaccording to claim 1 selected from the group consisting of:(5S)-2-Amino-5-[4-(difluoromethoxy)phenyl]-3-methyl-5-phenyl-3,5-dihydro-4H-imidazol-4-one;(5R)-2-Amino-5-[4-(difluoromethoxy)-phenyl]-3-methyl-5-phenyl-3,5-dihydro-4H-imidazol-4-one;(5R)-2-Amino-5-[4-(difluoromethoxy)phenyl]-3-methyl-5-(3-propylphenyl)-3,5-dihydro-4H-imidazol-4-one;(5S)-2-Amino-5-[4-(difluoromethoxy)phenyl]-3-methyl-5-(3-propylphenyl)-3,5-dihydro-4H-imidazol-4-one;2-Amino-5-[4-(difluoromethoxy)phenyl]-5-[3-(3-fluoropropyl)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one;2-Amino-5-[4-(difluoromethoxy)phenyl]-5-[3-(3,3-difluoropropyl)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one;2-Amino-5-[4-(difluoromethoxy)phenyl]-5-[3-(4-fluorobutyl)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one;2-Amino-5-[3-(4,4-difluorobutyl)phenyl]-5-[4-(difluoromethoxy)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one;2-Amino-5-[4-(difluoromethoxy)phenyl]-5-[3-(2-fluoroethyl)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one;2-Amino-5-[3-(2,2-difluoroethyl)phenyl]-5-[4-(difluoromethoxy)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one;2-Amino-5-[4-(difluoromethoxy)phenyl]-3-methyl-5-[3-(2,2,2-trifluoroethyl)phenyl]-3,5-dihydro-4H-imidazol-4-one;2-Amino-5-[4-(difluoromethoxy)phenyl]-3-methyl-5-[3-(3,3,3-trifluoropropyl)phenyl]-3,5-dihydro-4H-imidazol-4-one;2-Amino-5-[4-(difluoromethoxy)phenyl]-3-methyl-5-[3-(4,4,4-trifluorobutyl)phenyl]-3,5-dihydro-4H-imidazol-4-one;(5R)-2-amino-5-(3-butylphenyl)-5-[4-(difluoromethoxy)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one;(5S)-2-amino-5-(3-butylphenyl)-5-[4-(difluoromethoxy)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one;2-Amino-5-[4-(difluoromethoxy)phenyl]-3-methyl-5-(3-pentylphenyl)-3,5-dihydro-4H-imidazol-4-one;2-Amino-5-[4-(difluoromethoxy)phenyl]-3-methyl-5-[3-(2-methylbutyl)phenyl]-3,5-dihydro-4H-imidazol-4-one;2-Amino-5-(3-but-3-en-1-ylphenyl)-5-[4-(difluoromethoxy)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one;2-Amino-5-[3-(cyclopropylmethyl)phenyl]-5-[4-(difluoromethoxy)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one;3-(3-{2-Amino-4-[4-(difluoromethoxy)phenyl]-1-methyl-5-oxo-4,5-dihydro-1H-imidazol-4-yl}phenyl)propanenitrile;(5R)-2-Amino-5-[4-(difluoromethoxy)phenyl]-3-methyl-5-(3-pent-4-en-1-ylphenyl)-3,5-dihydro-4H-imidazol-4-one;(5S)-2-Amino-5-[4-(difluoromethoxy)phenyl]-3-methyl-5-(3-pent-4-en-1-ylphenyl)-3,5-dihydro-4H-imidazol-4-one;N-(3-{(4R)-2-Amino-4-[4-(difluoromethoxy)phenyl]-1-methyl-5-oxo-4,5-dihydro-1H-imidazol-4-yl}phenyl)-2-methoxyacetamide;N-(3-{(4S)-2-Amino-4-[4-(difluoromethoxy)phenyl]-1-methyl-5-oxo-4,5-dihydro-1H-imidazol-4-yl}phenyl)-2-methoxyacetamide;(5S)-2-amino-5-[4-(difluoromethoxy)phenyl]-3-methyl-5-phenyl-3,5-dihydro-4H-imidazol-4-one;2-amino-5-[4-(difluoromethoxy)phenyl]-5-[3-(4-hydroxybut-1-yn-1-yl)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one;2-amino-5-[4-(difluoromethoxy)phenyl]-5-[3-(4-hydroxybutyl)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one;2-amino-5-[4-(difluoromethoxy)phenyl]-5-[3-(5-fluoropentyl)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one;2-amino-5-[4-(difluoromethoxy)phenyl]-5-[3-(4-fluorobutyl)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one;2-amino-5-[4-(difluoromethoxy)phenyl]-5-[3-(6-fluorohexyl)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one;2-amino-5-[4-(difluoromethoxy)phenyl]-5-[3-(4-methoxybutyl)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one;2-amino-5-[4-(difluoromethoxy)phenyl]-5-{3-[(1Z)-3-methoxyprop-1-en-1-yl]phenyl}-3-methyl-3,5-dihydro-4H-imidazol-4-one;2-amino-5-[4-(difluoromethoxy)phenyl]-5-[3-(3-methoxypropyl)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one;2-amino-5-[3-(4,4-difluorobutyl)phenyl]-5-[4-(difluoromethoxy)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one;3-{2-amino-4-[4-(difluoromethoxy)phenyl]-1-methyl-5-oxo-4,5-dihydro-1H-imidazol-4-yl}-N-propylbenzamide;2-amino-5-[4-(difluoromethoxy)phenyl]-5-{3-[(2-fluoroethoxy)methyl]phenyl}-3-methyl-3,5-dihydro-4H-imidazol-4-one;2-amino-5-[4-(difluoromethoxy)phenyl]-3-methyl-5-{3-[(3,3,3-trifluoropropoxy)methyl]phenyl}-3,5-dihydro-4H-imidazol-4-one;2-amino-5-[4-(difluoromethoxy)phenyl]-5-[3-(methoxymethyl)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one;2-amino-5-[3-(butoxymethyl)phenyl]-5-[4-(difluoromethoxy)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one;2-amino-5-{3-[(cyclopropylmethoxy)methyl]phenyl}-5-[4-(difluoromethoxy)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one;2-amino-5-[4-(difluoromethoxy)phenyl]-5-[3-(ethoxymethyl)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one;2-amino-5-[4-(difluoromethoxy)phenyl]-3-methyl-5-[3-(propoxymethyl)phenyl]-3,5-dihydro-4H-imidazol-4-one;2-amino-5-[4-(difluoromethoxy)phenyl]-5-(3-{[2-fluoro-1-(fluoromethyl)ethoxy]methyl}phenyl)-3-methyl-3,5-dihydro-4H-imidazol-4-one;2-amino-5-[4-(difluoromethoxy)phenyl]-3-methyl-5-{3-[(2,2,2-trifluoroethoxy)methyl]phenyl}-3,5-dihydro-4H-imidazol-4-one;2-amino-5-[4-(difluoromethoxy)phenyl]-3-methyl-5-{3-[(2,2,3,3-tetrafluoropropoxy)methyl]phenyl}-3,5-dihydro-4H-imidazol-4-one;4-[4-(difluoromethoxy)phenyl]-4-[3-(3-methoxyprop-1-yn-1-yl)phenyl]-1-methyl-4,5-dihydro-1H-imidazol-2-amine;2-amino-5-[3-(1,4-difluorobutyl)phenyl]-5-[4-(difluoromethoxy)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one;2-amino-5-[4-(difluoromethoxy)phenyl]-5-[3-(3-fluorobut-3-en-1-yl)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one;2-amino-5-[3-(4,4-difluorobut-3-en-1-yl)phenyl]-5-[4-(difluoromethoxy)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one;2-amino-5-[4-(difluoromethoxy)phenyl]-3-methyl-5-[3-(4,4,4-trifluorobutyl)phenyl]-3,5-dihydro-4H-imidazol-4-one;5-(3-{2-amino-4-[4-(difluoromethoxy)phenyl]-1-methyl-5-oxo-4,5-dihydro-1H-imidazol-4-yl}phenyl)pentanenitrile;4-(3-{2-amino-4-[4-(difluoromethoxy)phenyl]-1-methyl-5-oxo-4,5-dihydro-1H-imidazol-4-yl}phenyl)butanenitrile;2-amino-5-{3-[(1E)-4,4-difluorobut-1-en-1-yl]phenyl}-5-[4-(difluoromethoxy)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one;2-amino-5-[4-(difluoromethoxy)phenyl]-5-[3-(3-hydroxyhex-4-yn-1-yl)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one;2-amino-5-[4-(difluoromethoxy)phenyl]-5-{3-[(1E)-6-methoxyhex-1-en-1-yl]phenyl}-3-methyl-3,5-dihydro-4H-imidazol-4-one;2-amino-5-[4-(difluoromethoxy)phenyl]-5-{3-[(1E)-5-methoxypent-1-en-1-yl]phenyl}-3-methyl-3,5-dihydro-4H-imidazol-4-one;2-amino-5-[4-(difluoromethoxy)phenyl]-5-{3-[2-(methoxymethyl)cyclopropyl]phenyl}-3-methyl-3,5-dihydro-4H-imidazol-4-one;2-amino-5-[4-(difluoromethoxy)phenyl]-5-{3-[(1E)-5-hydroxypent-1-en-1-yl}phenyl}-3-methyl-3,5-dihydro-4H-imidazol-4-one;2-amino-5-[4-(difluoromethoxy)phenyl]-5-{3-[(1E)-3-methoxyprop-1-en-1-yl]phenyl}-3-methyl-3,5-dihydro-4H-imidazol-4-one;2-amino-5-[4-(difluoromethoxy)phenyl]-5-{3-[(1E)-4-methoxybut-1-en-1-yl]phenyl}-3-methyl-3,5-dihydro-4H-imidazol-4-one;2-amino-5-[4-(difluoromethoxy)phenyl]-5-{3-[(1E)-4-hydroxybut-1-en-1-yl]phenyl}-3-methyl-3,5-dihydro-4H-imidazol-4-one;2-amino-5-[4-(difluoromethoxy)phenyl]-5-{3-[2-(2-methoxyethyl)cyclopropyl]phenyl}-3-methyl-3,5-dihydro-4H-imidazol-4-one;2-amino-5-[4-(difluoromethoxy)phenyl]-5-{3-[(1E)-4-fluorobut-1-en-1-yl]phenyl}-3-methyl-3,5-dihydro-4H-imidazol-4-one;2-amino-5-[4-(difluoromethoxy)phenyl]-5-{3-[(1E)-5-fluoropent-1-en-1-yl]phenyl}-3-methyl-3,5-dihydro-4H-imidazol-4-one;5-(3-acetylphenyl)-2-amino-5-[4-(difluoromethoxy)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one;2-amino-5-[4-(difluoromethoxy)phenyl]-5-{4-fluoro-3-[(1E)-4-fluorobut-1-en-1-yl]phenyl}-3-methyl-3,5-dihydro-4H-imidazol-4-one;2-amino-5-[4-(difluoromethoxy)phenyl]-5-[3-(3-fluoroprop-1-yn-1-yl)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one;2-amino-5-[4-(difluoromethoxy)phenyl]-5-(3-hydroxyphenyl)-3-methyl-3,5-dihydro-4H-imidazol-4-one;2-amino-5-[4-(difluoromethoxy)phenyl]-5-[3-(3-fluoropropoxy)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one;2-amino-5-[3-(cyclopropylmethoxy)phenyl]-5-[4-(difluoromethoxy)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one;2-amino-5-[4-(difluoromethoxy)phenyl]-3-methyl-5-[3-(4,4,4-trifluorobutoxy)phenyl]-3,5-dihydro-4H-imidazol-4-one;2-amino-5-[3-(2,2-difluoroethoxy)phenyl]-5-[4-(difluoromethoxy)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one;2-amino-5-[4-(difluoromethoxy)phenyl]-5-[3-(4-fluorobutoxy)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one;2-amino-5-[4-(difluoromethoxy)phenyl]-3-methyl-5-[3-(3-phenoxypropoxy)phenyl]-3,5-dihydro-4H-imidazol-4-one;4-(3-{2-amino-4-[4-(difluoromethoxy)phenyl]-1-methyl-5-oxo-4,5-dihydro-1H-imidazol-4-yl}phenoxy)butanenitrile;2-amino-5-[4-(difluoromethoxy)phenyl]-5-[4-fluoro-3-(3-fluoropropoxy)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one;2-amino-5-[3-(but-2-yn-1-yloxy)-4-fluorophenyl]-5-[4-(difluoromethoxy)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one;2-amino-5-[4-(difluoromethoxy)phenyl]-5-[4-fluoro-3-(4-fluorobutoxy)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one;2-amino-5-[3-(2,2-difluoroethoxy)-4-fluorophenyl]-5-[4-(difluoromethoxy)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one;(5R)-2-amino-5-[4-(difluoromethoxy)phenyl]-5-[4-fluoro-3-(3-fluoropropoxy)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one;(5S)-2-amino-5-[4-(difluoromethoxy)phenyl]-5-[4-fluoro-3-(3-fluoropropoxy)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one;2-amino-5-{3-[(4,4-difluorobut-3-en-1-yl)oxy]phenyl}-5-[4-(difluoromethoxy)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one;(5S)-2-amino-5-[3-(2,2-difluoroethoxy)-4-fluorophenyl]-5-[4-(difluoromethoxy)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one;(5R)-2-amino-5-[3-(2,2-difluoromethoxy)-4-fluorophenyl]-5-[4-(difluoromethoxy)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one;2-amino-5-[4-(difluoromethoxy)phenyl]-5-[3-(2-fluoroethyl)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-one;2-amino-5-[4-(difluoromethoxy)phenyl]-5-[3-(5-fluoropentanoyl)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one;2-amino-5-[4-(difluoromethoxy)phenyl]-5-[3-(4-fluorobutanoyl)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one;2-amino-5-[3-(but-3-en-1-yloxy)phenyl]-5-[4-(difluoromethoxy)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one;2-amino-5-[3-(but-3-en-1-yloxy)-4-fluorophenyl]-5-[4-(difluoromethoxy)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one;(5R)-2-amino-5-[3-(but-3-en-1-yloxy)phenyl]-5-[4-(difluoromethoxy)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one;(5S)-2-amino-5-[3-(but-3-en-1-yloxy)phenyl]-5-[4-(difluoromethoxy)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one;2-amino-5-{3-[(4,4-difluorobut-3-en-1-yl)oxy]-4-fluorophenyl}-5-[4-(difluoromethoxy)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one;2-amino-5-[4-(difluoromethoxy)phenyl]-5-(4-fluoro-3-pent-4-en-1-ylphenyl)-3-methyl-3,5-dihydro-4H-imidazol-4-one;2-amino-5-(3-but-3-en-1-yl-4-fluorophenyl)-5-[4-(difluoromethoxy)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one;3-{2-amino-4-[4-(difluoromethoxy)phenyl]-1-methyl-5-oxo-4,5-dihydro-1H-imidazol-4-yl}benzaldehyde;2-amino-5-[4-(difluoromethoxy)phenyl]-5-[3-(1-hydroxybut-2-yn-1-yl)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one;2-amino-5-[4-(difluoromethoxy)phenyl]-5-[3-(1,4-dihydroxybut-2-yn-1-yl)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one;(5R)-2-amino-5-[3-(difluoromethoxy)phenyl]-5-[4-(difluoromethoxy)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one;2-amino-5-[4-(difluoromethoxy)phenyl]-5-[3-(2,2-dimethyl-3-oxocyclobutyl)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one;2-amino-5-[4-(difluoromethoxy)phenyl]-3-methyl-5-[3-(3-oxocyclobutyl)phenyl]-3,5-dihydro-4H-imidazol-4-one;2-amino-5-[4-(difluoromethoxy)phenyl]-5-[3-(3-hydroxycyclobutyl)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one;methyl[3-(3-{2-amino-4-[4-(difluoromethoxy)phenyl]-1-methyl-5-oxo-4,5-dihydro-1H-imidazol-4-yl}phenyl)cyclobutyl]acetate;and methyl(3-(3-{2-amino-4-[4-(difluoromethoxy)phenyl]-1-methyl-5-oxo-4,5-dihydro-1H-imidazol-4-yl}phenyl)cyclobutylidene]acetate;a tautomer thereof; a stereoisomer thereof; and a pharmaceuticallyacceptable salt thereof.
 10. A pharmaceutical composition whichcomprises a pharmaceutically acceptable carrier and an effective amountof a compound of formula I

wherein R₁ and R₂ are each independently H or an alkyl, cycloalkyl,cycloheteroalkyl, aryl or heteroaryl group each optionally substitutedor R₁ and R₂ may be taken together with the atom to which they areattached to form an optionally substituted 5- to 7-membered ringoptionally interrupted by an additional heteroatom selected from O, N orS; R₃ is H or an alkyl, cycloalkyl, cycloheteroalkyl, aryl or heteroarylgroup each optionally substituted; R₄, R₅ and R₆ are each independentlyH, halogen, NO₂, CN, COR₇, NR₁₀CO₂R₁₁, NR₁₅COR₁₆, OR₁₄, NR₁₂R₁₃,SO_(n)R₁₇ or an alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl,cycloalkyl or cycloheteroalkyl group each optionally substituted or whenattached to adjacent carbon atoms R₄ and R₅ may be taken together withthe atoms to which they are attached to form an optionally substituted5- to 7-membered ring optionally containing one or two heteroatomsselected from O, N or S; n is 0, 1 or 2; R₇ and R₁₇ are eachindependently H, NR₈R₉ or an alkyl, haloalkyl, alkoxyalkyl, alkenyl,alkynyl, cycloalkyl or aryl group each optionally substituted; R₈ and R₉are each independently H or an alkyl, alkenyl, alkynyl or cycloalkylgroup each optionally substituted or R₈ and R₉ may be taken togetherwith the atom to which they are attached to form an optionallysubstituted 5- to 7-membered ring optionally containing an additionalheteroatom selected from O, N or S; R₁₁, R₁₄ and R₁₆ are eachindependently H or an alkyl, haloalkyl, alkoxyalkyl, alkenyl, alkynyl,cycloalkyl or aryl group each optionally substituted; R₁₀ and R₁₅ areeach independently H or an optionally substituted alkyl group; and R₁₂and R₁₃ are each independently H or an alkyl or cycloalkyl group eachoptionally substituted or R₁₂ and R₁₃ may be taken together with theatom to which they are attached to form an optionally substituted 5- to7-membered ring optionally containing an additional heteroatom selectedfrom O, N or S; or a tautomer thereof, a stereoisomer thereof or apharmaceutically acceptable salt thereof.
 11. The composition accordingto claim 10 having a formula I compound wherein R₁ and R₂ are H.
 12. Thecomposition according to claim 11 having a formula I compound wherein R₃is C₁-C₄alkyl.
 13. The composition according to claim 12 having aformula I compound wherein R₄, R₅ and R₆ are each independently H,halogen, COR₇, OR₁₄, or an alkyl, haloalkyl, alkoxy, haloalkoxy, alkynylor cycloalkyl group each optionally substituted.
 14. The compositionaccording to claim 13 having a formula I compound wherein R₄ is at the3-position of the phenyl ring; and R₅ and R₆ are each independently H orhalogen.
 15. The composition according to claim 10 having a formula Icompound selected from the group consisting of:(5S)-2-Amino-5-[4-(difluoromethoxy)phenyl]-3-methyl-5-phenyl-3,5-dihydro-4H-imidazol-4-one;(5R)-2-Amino-5-[4-(difluoromethoxy)-phenyl]-3-methyl-5-phenyl-3,5-dihydro-4H-imidazol-4-one;(5R)-2-Amino-5-[4-(difluoromethoxy)phenyl]-3-methyl-5-(3-propylphenyl)-3,5-dihydro-4H-imidazol-4-one;(5S)-2-Amino-5-[4-(difluoromethoxy)phenyl]-3-methyl-5-(3-propylphenyl)-3,5-dihydro-4H-imidazol-4-one;2-Amino-5-[4-(difluoromethoxy)phenyl]-5-[3-(3-fluoropropyl)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one;2-Amino-5-[4-(difluoromethoxy)phenyl]-5-[3-(3,3-difluoropropyl)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one;2-Amino-5-[4-(difluoromethoxy)phenyl]-5-[3-(4-fluorobutyl)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one;2-Amino-5-[3-(4,4-difluorobutyl)phenyl]-5-[4-(difluoromethoxy)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one;2-Amino-5-[4-(difluoromethoxy)phenyl]-5-[3-(2-fluoroethyl)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one;2-Amino-5-[3-(2,2-difluoroethyl)phenyl]-5-[4-(difluoromethoxy)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one;2-Amino-5-[4-(difluoromethoxy)phenyl]-3-methyl-5-[3-(2,2,2-trifluoroethyl)phenyl]-3,5-dihydro-4H-imidazol-4-one;2-Amino-5-[4-(difluoromethoxy)phenyl]-3-methyl-5-[3-(3,3,3-trifluoropropyl)phenyl]-3,5-dihydro-4H-imidazol-4-one;2-Amino-5-[4-(difluoromethoxy)phenyl]-3-methyl-5-[3-(4,4,4-trifluorobutyl)phenyl]-3,5-dihydro-4H-imidazol-4-one;(5R)-2-amino-5-(3-butylphenyl)-5-[4-(difluoromethoxy)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one;(5S)-2-amino-5-(3-butylphenyl)-5-[4-(difluoromethoxy)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one;2-Amino-5-[4-(difluoromethoxy)phenyl]-3-methyl-5-(3-pentylphenyl)-3,5-dihydro-4H-imidazol-4-one;2-Amino-5-[4-(difluoromethoxy)phenyl]-3-methyl-5-[3-(2-methylbutyl)phenyl]-3,5-dihydro-4H-imidazol-4-one;2-Amino-5-(3-but-3-en-1-ylphenyl)-5-[4-(difluoromethoxy)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one;2-Amino-5-[3-(cyclopropylmethyl)phenyl]-5-[4-(difluoromethoxy)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one;3-(3-{2-Amino-4-[4-(difluoromethoxy)phenyl]-1-methyl-5-oxo-4,5-dihydro-1H-imidazol-4-yl}phenyl)propanenitrile;(5R)-2-Amino-5-[4-(difluoromethoxy)phenyl]-3-methyl-5-(3-pent-4-en-1-ylphenyl)-3,5-dihydro-4H-imidazol-4-one;(5S)-2-Amino-5-[4-(difluoromethoxy)phenyl]-3-methyl-5-(3-pent-4-en-1-ylphenyl)-3,5-dihydro-4H-imidazol-4-one;N-(3-{(4R)-2-Amino-4-[4-(difluoromethoxy)phenyl]-1-methyl-5-oxo-4,5-dihydro-1H-imidazol-4-yl}phenyl)-2-methoxyacetamide;N-(3-{(4S)-2-Amino-4-[4-(difluoromethoxy)phenyl]-1-methyl-5-oxo-4,5-dihydro-1H-imidazol-4-yl}phenyl)-2-methoxyacetamide;(5S)-2-amino-5-[4-(difluoromethoxy)phenyl]-3-methyl-5-phenyl-3,5-dihydro-4H-imidazol-4-one;2-amino-5-[4-(difluoromethoxy)phenyl]-5-[3-(4-hydroxybut-1-yn-1-yl)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one;2-amino-5-[4-(difluoromethoxy)phenyl]-5-[3-(4-hydroxybutyl)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one;2-amino-5-[4-(difluoromethoxy)phenyl]-5-[3-(5-fluoropentyl)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one;2-amino-5-[4-(difluoromethoxy)phenyl]-5-[3-(4-fluorobutyl)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one;2-amino-5-[4-(difluoromethoxy)phenyl]-5-[3-(6-fluorohexyl)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one;2-amino-5-[4-(difluoromethoxy)phenyl]-5-[3-(4-methoxybutyl)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one;2-amino-5-[4-(difluoromethoxy)phenyl]-5-{3-[(1Z)-3-methoxyprop-1-en-1-yl]phenyl}-3-methyl-3,5-dihydro-4H-imidazol-4-one;2-amino-5-[4-(difluoromethoxy)phenyl]-5-[3-(3-methoxypropyl)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one;2-amino-5-[3-(4,4-difluorobutyl)phenyl]-5-[4-(difluoromethoxy)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one;3-{2-amino-4-[4-(difluoromethoxy)phenyl]-1-methyl-5-oxo-4,5-dihydro-1H-imidazol-4-yl}-N-propylbenzamide;2-amino-5-[4-(difluoromethoxy)phenyl]-5-{3-[(2-fluoroethoxy)methyl]phenyl}-3-methyl-3,5-dihydro-4H-imidazol-4-one;2-amino-5-[4-(difluoromethoxy)phenyl]-3-methyl-5-{3-[(3,3,3-trifluoropropoxy)methyl]phenyl}-3,5-dihydro-4H-imidazol-4-one;2-amino-5-[4-(difluoromethoxy)phenyl]-5-[3-(methoxymethyl)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one;2-amino-5-[3-(butoxymethyl)phenyl]-5-[4-(difluoromethoxy)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one;2-amino-5-{3-[(cyclopropylmethoxy)methyl]phenyl}-5-[4-(difluoromethoxy)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one;2-amino-5-[4-(difluoromethoxy)phenyl]-5-[3-(ethoxymethyl)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one;2-amino-5-[4-(difluoromethoxy)phenyl]-3-methyl-5-[3-(propoxymethyl)phenyl]-3,5-dihydro-4H-imidazol-4-one;2-amino-5-[4-(difluoromethoxy)phenyl]-5-(3-{[2-fluoro-1-(fluoromethyl)ethoxy]methyl}phenyl)-3-methyl-3,5-dihydro-4H-imidazol-4-one;2-amino-5-[4-(difluoromethoxy)phenyl]-3-methyl-5-{3-[(2,2,2-trifluoroethoxy)methyl]phenyl}-3,5-dihydro-4H-imidazol-4-one;2-amino-5-[4-(difluoromethoxy)phenyl]-3-methyl-5-{3-[(2,2,3,3-tetrafluoropropoxy)methyl]phenyl}-3,5-dihydro-4H-imidazol-4-one;4-[4-(difluoromethoxy)phenyl]-4-[3-(3-methoxyprop-1-yn-1-yl)phenyl]-1-methyl-4,5-dihydro-1H-imidazol-2-amine;2-amino-5-[3-(1,4-difluorobutyl)phenyl]-5-[4-(difluoromethoxy)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one;2-amino-5-[4-(difluoromethoxy)phenyl]-5-[3-(3-fluorobut-3-en-1-yl)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one;2-amino-5-[3-(4,4-difluorobut-3-en-1-yl)phenyl]-5-[4-(difluoromethoxy)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one;2-amino-5-[4-(difluoromethoxy)phenyl]-3-methyl-5-[3-(4,4,4-trifluorobutyl)phenyl]-3,5-dihydro-4H-imidazol-4-one;5-(3-{2-amino-4-[4-(difluoromethoxy)phenyl]-1-methyl-5-oxo-4,5-dihydro-1H-imidazol-4-yl}phenyl)pentanenitrile;4-(3-{2-amino-4-[4-(difluoromethoxy)phenyl]-1-methyl-5-oxo-4,5-dihydro-1H-imidazol-4-yl}phenyl)butanenitrile;2-amino-5-{3-[(1E)-4,4-difluorobut-1-en-1-yl]phenyl}-5-[4-(difluoromethoxy)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one;2-amino-5-[4-(difluoromethoxy)phenyl]-5-[3-(3-hydroxyhex-4-yn-1-yl)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one;2-amino-5-[4-(difluoromethoxy)phenyl]-5-{3-[(1E)-6-methoxyhex-1-en-1-yl]phenyl}-3-methyl-3,5-dihydro-4H-imidazol-4-one;2-amino-5-[4-(difluoromethoxy)phenyl]-5-{3-[(1E)-5-methoxypent-1-en-1-yl]phenyl}-3-methyl-3,5-dihydro-4H-imidazol-4-one;2-amino-5-[4-(difluoromethoxy)phenyl]-5-{3-[2-(methoxymethyl)cyclopropyl]phenyl}-3-methyl-3,5-dihydro-4H-imidazol-4-one;2-amino-5-[4-(difluoromethoxy)phenyl]-5-{3-[(1E)-5-hydroxypent-1-en-1-yl}phenyl}-3-methyl-3,5-dihydro-4H-imidazol-4-one;2-amino-5-[4-(difluoromethoxy)phenyl]-5-{3-[(1E)-3-methoxyprop-1-en-1-yl]phenyl}-3-methyl-3,5-dihydro-4H-imidazol-4-one;2-amino-5-[4-(difluoromethoxy)phenyl]-5-{3-[(1E)-4-methoxybut-1-en-1-yl]phenyl}-3-methyl-3,5-dihydro-4H-imidazol-4-one;2-amino-5-[4-(difluoromethoxy)phenyl]-5-{3-[(1E)-4-hydroxybut-1-en-1-yl]phenyl}-3-methyl-3,5-dihydro-4H-imidazol-4-one;2-amino-5-[4-(difluoromethoxy)phenyl]-5-{3-[2-(2-methoxyethyl)cyclopropyl]phenyl}-3-methyl-3,5-dihydro-4H-imidazol-4-one;2-amino-5-[4-(difluoromethoxy)phenyl]-5-{3-[(1E)-4-fluorobut-1-en-1-yl]phenyl}-3-methyl-3,5-dihydro-4H-imidazol-4-one;2-amino-5-[4-(difluoromethoxy)phenyl]-5-{3-[(1E)-5-fluoropent-1-en-1-yl]phenyl}-3-methyl-3,5-dihydro-4H-imidazol-4-one;5-(3-acetylphenyl)-2-amino-5-[4-(difluoromethoxy)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one;2-amino-5-[4-(difluoromethoxy)phenyl]-5-{4-fluoro-3-[(1E)-4-fluorobut-1-en-1-yl]phenyl}-3-methyl-3,5-dihydro-4H-imidazol-4-one;2-amino-5-[4-(difluoromethoxy)phenyl]-5-[3-(3-fluoroprop-1-yn-1-yl)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one;2-amino-5-[4-(difluoromethoxy)phenyl]-5-(3-hydroxyphenyl)-3-methyl-3,5-dihydro-4H-imidazol-4-one;2-amino-5-[4-(difluoromethoxy)phenyl]-5-[3-(3-fluoropropoxy)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one;2-amino-5-[3-(cyclopropylmethoxy)phenyl]-5-[4-(difluoromethoxy)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one;2-amino-5-[4-(difluoromethoxy)phenyl]-3-methyl-5-[3-(4,4,4-trifluorobutoxy)phenyl]-3,5-dihydro-4H-imidazol-4-one;2-amino-5-[3-(2,2-difluoroethoxy)phenyl]-5-[4-(difluoromethoxy)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one;2-amino-5-[4-(difluoromethoxy)phenyl]-5-[3-(4-fluorobutoxy)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one;2-amino-5-[4-(difluoromethoxy)phenyl]-3-methyl-5-[3-(3-phenoxypropoxy)phenyl]-3,5-dihydro-4H-imidazol-4-one;4-(3-{2-amino-4-[4-(difluoromethoxy)phenyl]-1-methyl-5-oxo-4,5-dihydro-1H-imidazol-4-yl}phenoxy)butanenitrile;2-amino-5-[4-(difluoromethoxy)phenyl]-5-[4-fluoro-3-(3-fluoropropoxy)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one;2-amino-5-[3-(but-2-yn-1-yloxy)-4-fluorophenyl]-5-[4-(difluoromethoxy)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one;2-amino-5-[4-(difluoromethoxy)phenyl]-5-[4-fluoro-3-(4-fluorobutoxy)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one;2-amino-5-[3-(2,2-difluoroethoxy)-4-fluorophenyl]-5-[4-(difluoromethoxy)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one;(5R)-2-amino-5-[4-(difluoromethoxy)phenyl]-5-[4-fluoro-3-(3-fluoropropoxy)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one;(5S)-2-amino-5-[4-(difluoromethoxy)phenyl]-5-[4-fluoro-3-(3-fluoropropoxy)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one;2-amino-5-{3-[(4,4-difluorobut-3-en-1-yl)oxy]phenyl}-5-[4-(difluoromethoxy)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one;(5S)-2-amino-5-[3-(2,2-difluoroethoxy)-4-fluorophenyl]-5-[4-(difluoromethoxy)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one;(5R)-2-amino-5-[3-(2,2-difluoromethoxy)-4-fluorophenyl]-5-[4-(difluoromethoxy)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one;2-amino-5-[4-(difluoromethoxy)phenyl]-5-[3-(2-fluoroethyl)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-one;2-amino-5-[4-(difluoromethoxy)phenyl]-5-[3-(5-fluoropentanoyl)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one;2-amino-5-[4-(difluoromethoxy)phenyl]-5-[3-(4-fluorobutanoyl)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one;2-amino-5-[3-(but-3-en-1-yloxy)phenyl]-5-[4-(difluoromethoxy)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one;2-amino-5-[3-(but-3-en-1-yloxy)-4-fluorophenyl]-5-[4-(difluoromethoxy)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one;(5R)-2-amino-5-[3-(but-3-en-1-yloxy)phenyl]-5-[4-(difluoromethoxy)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one;(5S)-2-amino-5-[3-(but-3-en-1-yloxy)phenyl]-5-[4-(difluoromethoxy)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one;2-amino-5-{3-[(4,4-difluorobut-3-en-1-yl)oxy]-4-fluorophenyl}-5-[4-(difluoromethoxy)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one;2-amino-5-[4-(difluoromethoxy)phenyl]-5-(4-fluoro-3-pent-4-en-1-ylphenyl)-3-methyl-3,5-dihydro-4H-imidazol-4-one;2-amino-5-(3-but-3-en-1-yl-4-fluorophenyl)-5-[4-(difluoromethoxy)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one;3-{2-amino-4-[4-(difluoromethoxy)phenyl]-1-methyl-5-oxo-4,5-dihydro-1H-imidazol-4-yl}benzaldehyde;2-amino-5-[4-(difluoromethoxy)phenyl]-5-[3-(1-hydroxybut-2-yn-1-yl)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one;2-amino-5-[4-(difluoromethoxy)phenyl]-5-[3-(1,4-dihydroxybut-2-yn-1-yl)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one;(5R)-2-amino-5-[3-(difluoromethoxy)phenyl]-5-[4-(difluoromethoxy)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one;2-amino-5-[4-(difluoromethoxy)phenyl]-5-[3-(2,2-dimethyl-3-oxocyclobutyl)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one;2-amino-5-[4-(difluoromethoxy)phenyl]-3-methyl-5-[3-(3-oxocyclobutyl)phenyl]-3,5-dihydro-4H-imidazol-4-one;2-amino-5-[4-(difluoromethoxy)phenyl]-5-[3-(3-hydroxycyclobutyl)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one;methyl[3-(3-{2-amino-4-[4-(difluoromethoxy)phenyl]-1-methyl-5-oxo-4,5-dihydro-1H-imidazol-4-yl}phenyl)cyclobutyl]acetate;and methyl[3-(3-{2-amino-4-[4-(difluoromethoxy)phenyl]-1-methyl-5-oxo-4,5-dihydro-1H-imidazol-4-yl}phenyl)cyclobutylidene]acetate;a tautomer thereof; a stereoisomer thereof; and a pharmaceuticallyacceptable salt thereof.